Introduction

Pheochromocytomas (PCs) and sympathetic paragangliomas (sPGLs) are rare neuroendocrine tumors, arising from chromaffin cells of the sympathoadrenal system, which autonomously synthesize and secrete catecholamines and their metabolites. According to recent epidemiological studies, their incidence is 0.57–0.66 cases per 100,000 person-years [1, 2] and it has increased over the last 20 years due to more frequent use of abdominal imaging, increased awareness and rate of suspicion for these disorders on the part of the medical community, as well as mutation-based case detection testing. These factors have led to earlier detection and an increasing number of PCs being diagnosed on the basis of imaging and genetic testing as opposed to symptom-recognition/clinical presentation [3].

Although the vast majority of PCs are catecholamine-secreting, in extremely rare cases, these tumors may demonstrate no functional activity. Biochemically silent PCs are characterized by normal catecholamine levels due to either lack of catecholamine production or subtle synthesis and secretion within the established normal levels [4]. They are mostly asymptomatic and they are discovered either incidentally on abdominal imaging or due to space-occupying complications; when malignant, they may present with symptoms of metastatic disease [5].

Data on the characteristics of patients with biochemically silent PCs are scarce and the clinical behavior of these tumors is poorly investigated, mainly due to their rarity. The aim of the present study was to review the clinical, hormonal and imaging characteristics of patients with biochemically silent PCs from two Endocrine centers and to assess the pre-, intra- and post-operative management of these tumors and their outcomes.

Patients and methods

Study design and patients

This was a retrospective case series study from two Greek Endocrine centers. The records of adult patients diagnosed with biochemically silent PCs between 2014 and 2021 and followed-up in each participating center were reviewed and clinical, laboratory and imaging data, as well as treatment outcomes were recorded. The study was retrospective in nature and involved no intervention beyond routine patient care. Data were collected on a dedicated proforma.

Histologically proven PCs were defined as biochemically silent if pre-operative 24 h urine fractionated metanephrine (MN) and normetanephrine (NMN) levels, determined by high-pressure liquid chromatography, were below the upper limit of their respective reference range, measured on two different occasions in order to minimize the possibility of false negative results. For each patient, 24 h urine MN and NMN levels were defined as the average value of the two different measurements. The first and the fourth quartiles of the 24 h urine MN and NMN normal values were classified as low- and high-normal levels, respectively, while the second and third quartiles were classified as normal levels.

Imaging analysis, pre-, intra- and post-operative management and follow-up of the patients were based on clinical practice guidelines and the expert opinions of radiologists, endocrinologists, anesthesiologists and surgeons with experience in the management of patients with adrenal disorders at each participating center [6, 7]. Disease progression was diagnosed on the basis of radiological appearances. Follow-up period was defined from the time of surgery until the last imaging.

Intra-operative parameters

During adrenal surgery, hemodynamic parameters (blood pressure and heart rate), as well as blood glucose levels were monitored. Intra-operative data were obtained by review of anesthetic charts. Arrhythmias were considered when treatment with antiarrhythmic drug was required. Intra-operative hypertensive crisis was defined as SBP ≥ 200 mmHg and need for vasodilator therapy. Intra-operative hypotension was considered when mean arterial blood pressure <60 mmHg and/or treatment with vasoconstrictors or intravenous fluids (crystalloid and/or colloid) was required. Hemodynamic instability was defined as one or more episodes of hypertensive crisis or hypotension during adrenal surgery [8].

The above intra-operative parameters were also evaluated in 40 consecutive biochemically active PCs managed with adrenal surgery. All of these cases were pre-operatively treated with alpha-adrenergic receptors blockade.

Statistical analysis

Statistical analysis was performed using the SPSS software package (SPSS Inc., version 23, Chicago, USA). Median (min, max) values were used to express the results in all cases and the x2-test was performed for the comparison of categorical variables. A two-tailed p value < 0.05 was considered statistically significant.

Results

Pre-operative characteristics of patients with biochemically silent PCs

Ten patients (5 men) were included in the study. Their pre-operative characteristics are shown in Table 1. The adrenal masses were incidentally discovered in all patients except from one who presented with paroxysmal hypertension, palpitations and postural hypotension. Seven cases had a history of arterial hypertension.

Table 1 Pre-operative characteristics of patients diagnosed with biochemically silent pheochromocytoma
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Adrenal tumors were unilateral in all cases (7 on the right side) with a median maximum size on imaging of 46 mm (17–125). Increased tumor density on pre-contrast CT imaging (≥20 Hounsfield units) or high signal intensity on T2-weighted MRI scan was found in all cases; cystic and/or necrotic component was evident in 7 cases. 123I-metaiodobenzylguanidine scintigraphy (MIBG) was performed in 4 cases and it was positive in all of them.

Regarding catecholamine secretion, 24 h urine MN and NMN levels were in the low-normal, normal and high-normal range in 4, 4 and 2 patients and in 1, 6 and 3 patients, respectively. All patients had normal renal function. Plasma free MN and NMN, as well as 24 h urine 3-methoxytyramine (3-MT) levels were not included in the diagnostic protocol of PCs/PGLs of both Endocrine centers, therefore they were not measured in any patient. Pre-operative serum chromogranin A (CgA) levels were measured only in one case and it was found 10-times higher the upper limit of normal.

Pre-operative alpha-adrenergic receptors blockade with phenoxybenzamine at a median total daily dose of 70 mg (20–100) was administered in 5 patients; four of them had positive pre-operative 123I-MIBG scan, while in the fifth one there was a high index of suspicion for PC based on imaging characteristics of the tumor. In two of them, terazocin was also offered, before phenoxybenzamine initiation, at a daily dose of 2 mg and 5 mg, respectively. Phenoxybenzamine was discontinued 24 h before the adrenal surgery. The median duration of alpha-adrenergic receptors blockade was 14 days (9–32).

Individual patients’ characteristics at diagnosis along with their intra- and post-operative management and follow-up are shown in Table 2.

Table 2 Individual patients’ characteristics at diagnosis along with their intra- and post-operative management and follow-up
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Intra-operative characteristics

Nine patients (90%) had one or more episodes of intra-operative hemodynamic instability, most commonly hypotension followed by hypertensive crisis (Table 2). Laparoscopic adrenalectomy was performed in 6 patients (cases 1, 2, 4–7) and open adrenalectomy in the remaining 4 ones.

Hypotension after adrenal vein ligation was developed in 8 patients (4 of them had not been treated pre-operatively with alpha-adrenergic receptor blockade). Normalization of blood pressure required use of vasoconstrictors (phenylephrine or noradrenaline) in 5 patients (pre-operative alpha-adrenergic receptors blockers were not offered in 3 of them), while in the other 3 only intravenous crystalloid and/or colloid fluids were administered. It should be mentioned that hypotension was of short duration and was successfully treated before extubation in all patients apart from one (case 7, Table 2), who had not been pre-operatively treated with phenoxybenzamine or terazocin, and who developed Takotsubo cardiomyopathy during surgery requiring admission in the cardiac intensive care unit.

Intra-operative hypertensive crisis requiring glyceryl trinitrate administration developed in 4 patients despite pre-operative treatment with alpha-adrenergic receptors blockade in 2 of them (Table 2). None of the patients developed intra-operative arrhythmias or hypoglycemia. Further statistical analysis between the two subgroups of biochemically silent PCs (treated vs non-treated with alpha-adrenergic blockade) was not performed due to small sample size.

Evaluation of the intra-operative characteristics of 40 consecutive patients with secreting PCs, who were pre-operatively treated with alpha-adrenergic blockade, revealed hypertensive crises and hypotensive episodes in 57.5% (23/40) and 37.5% (15/40) of them, respectively; none of the patients developed intra-operative arrhythmias or hypoglycemia.

After comparing patients with silent PCs, who were offered pre-operative treatment with phenoxybenzamine, vs secreting ones, no statistically significant difference in the rates of hypertensive crisis (p = 0.64) and hypotension (p = 0.14) was found between the two groups. Same findings were also observed when patients with silent PCs, not pre-operatively managed with alpha-adrenergic receptors blockade, were compared with non-silent ones [hypertensive crisis (p = 0.64) and hypotension (p = 0.14)]. With regard to intra-operative hypoglycemia and arrhythmias, no comparison between biochemically silent and non-silent PCs was performed given that none of the patients in both groups developed any episodes.

Post-operative outcomes and follow-up

Complete tumor excision was achieved in all cases. Apart from the patient who developed Takotsubo cardiomyopathy, none of the other patients developed any episodes of hemodynamic instability during the post-operative period and there was no need for further administration of vasoconstrictors. Histology was diagnostic for PC in all patients and PASS score was ≥4 in all but one cases (2–9) (Table 2).

Testing for genetic syndromes known to be associated with PC was individually considered in each patient. Taking into account that PCs were unilateral in all cases and that, at the time at diagnosis, none of the patients had any syndromic or malignant features and no positive family history for any hereditary syndromes associated with PC, genetic testing was performed only in one patient (case 4, Table 2) due to young age. Genotyping of SDHB, VHL, RET was negative.

Median follow-up from the time of adrenal surgery until last imaging was 24 months (12–88). Post-operative 24 h urine MN and NMN levels were in the low-normal, normal and high-normal range in 5, 5, and 0 patients and in 5, 3 and 2 patients, respectively. During this period, disease progression was observed in one patient, 88 months after his initial surgery. A 2.9 cm right retroperitoneal para-aortic histologically-proven metastasis was detected with no local recurrence in the adrenal bed. At the time of disease progression 24 h urine MN and NMN levels were again normal.

In the only patient who pre-operatively presented with PC-related symptoms, adrenal surgery led to the resolution of all symptoms, as well as normalization of blood pressure levels.

Discussion

To our knowledge, this is the first case series systematically reviewing the clinical and imaging characteristics of patients with biochemically silent PCs and assessing their pre-, intra- and post-operative management and outcomes. We found that patients with biochemically silent PCs were in the vast majority asymptomatic and incidentally diagnosed (90%) due to lesions suspicious for PC on CT or MRI imaging. Importantly, 90% of the patients experienced at least one episode of hemodynamic instability during adrenal surgery, despite their tumors being biochemically inactive.

Biochemically silent PCs are very rare and published literature assessing the characteristics and the management of patients with this condition is extremely limited. We performed a literature search of Pubmed (up to 31/Dec/2021) using the term ‘silent pheochromocytoma’ and we identified only 12 reports [[3, 9,10,11,12,13,14,15,16,17,18,19], including 22 patients in total] assessing patients with histology-proven PCs and negative 24 h urine and/or plasma MN and NMN. Their pre-operative characteristics and management, as well as their intra-operative behavior and outcomes are presented in Table 3.

Table 3 Pre-operative characteristics and management, intra-operative complications and outcomes of patients with biochemically silent pheochromocytomas in the published literature
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Patients with secreting PCs may present with a broad spectrum of symptoms including the classic triad of headaches, palpitations, and sweating, as well as symptoms of anxiety and panic attacks, cardiomyopathy or even heart failure [20]. In biochemically silent PCs, one would expect patients to be asymptomatic. Despite this being the case in the vast majority of our patients (90%) and of those published in the literature (Table 3), four patients in the study by Gruber et al. and one of ours presented with PC-related symptoms [3]. Whether these patients had periodically-secreting PCs or their MN and NMN levels were falsely normal cannot be elucidated. It should be noted, however, that in our case, 24 h urine MN and NMN levels were well within the normal range (not even in the high-normal) on 3 different occasions, when the patient was symptomatic.

Detection of biochemically silent PCs is mostly incidental [10, 11, 13, 15,16,17, 19] or on the basis of germline-mutation testing [3, 9, 18]. In all published cases (including ours), tumors were unilateral, apart from 2 patients in whom bilateral biochemically silent PCs have been described; one patient had multiple endocrine neoplasia type 2 A (MEN2A) [3], while in the other no genetic testing was performed [17]. Tumors had an unenhanced CT density >20 Hounsfield units [3, 11], while in others hyperintensity on T2-weighted MRI images was reported [3, 19]; cystic changes and necrosis were also common [13, 15,16,17, 19]. These findings are in accordance with the imaging features of our patients.

The management of biochemically silent PCs is challenging. In secreting PCs, pre-operative alpha-adrenergic receptors blockade, for the prevention of intra-operative hypertension, tachycardia, and hemodynamic instability, and blood volume restoration, in order to decrease the risk of protracted hypotension as a result of sudden vasodilation during surgery, are recommended [21]. However, the pre-operative use of alpha-adrenergic receptors blockers is currently challenged mainly due to the post-operative sustained hypotension that can manifest as a complication of these agents [22, 23]. Although unexpected, malignant hypertension during adrenal surgery has been described in some [11, 16, 17] but not all [9, 13, 15, 19] patients with biochemically inactive PCs, as well as hypotensive episodes after adrenal vein ligation [16, 17]; none of these patients were pre-operatively treated with alpha-adrenergic receptor blockers. In our series, 90% of the patients developed intra-operative hemodynamic instability. Hypotension presented in 8 patients (half of them were treated with pre-operative alpha-adrenergic receptors blockers) and hypertensive crises in 4 patients, despite pre-operative treatment with adrenergic blockade in 2 of them. Notably, in one case, intra-operative hemodynamic instability was very severe and the patient developed Takotsubo cardiomyopathy. Although not elucidated yet, a possible mechanism for the intra-operative behaviour of biochemically silent PCs is that they might harbor significant intra-tumoral catecholamine reserve which is discharged during surgical tumor manipulations [22]. Interestingly, we did not identify any statistically significant differences in the rate of intra-operative hemodynamic instability (hypotension or hypertensive crisis) when we compared biochemically silent who were offered pre-operative treatment with non-silent PCs. However, these findings should be interpreted with caution given the small number of patients with biochemically silent PCs pre-operatively managed with or without alpha-adrenergic blockade.

Follow-up of patients with biochemically silent PCs is usually individualized and due to the scarce relevant literature, there is a lack of evidence-based recommendations. According to the 2016 ESE pheochromocytoma guidelines, these patients should be followed-up for disease progression with imaging every 1–2 years [24]; the authors, however, acknowledge that this time interval is arbitrary due the absence of observational or randomized studies on non-functioning PCs. Only one of our patients had disease progression during a 24-month median period of follow-up. He developed a right retroperitoneal para-aortic metastasis 88 months after his initial surgery. Metastatic disease progression of a biochemically silent PC has been also reported in a SDHD mutation carrier, who developed mediastinal and infrahilar lymph node metastases 4 months after surgery and a lytic vertebral bone metastasis 3 years later [18]. In addition, 7 patients with metastatic PCs (2 with SDHB mutations and 5 with apparently sporadic tumors) and normal 24 h urine MN and NMN levels [14], as well as a case of apparently sporadic biochemically silent PC who presented with metastatic disease at diagnosis [3] have been reported. CgA was measured in the pre- and post-operative state only in 3 patients (one in our series and in two case reports [13, 19], therefore, robust conclusions about the validity and reliability of CgA as an alternative biochemical marker for the monitoring of patients with biochemically silent PCs is not possible.

The pathogenetic mechanisms for the functional inactivity of biochemical silent PCs are not completely understood and several theories have been proposed. One hypothesis is that these tumors do not secrete catecholamines but instead they metabolize them to inactive compounds [5, 11, 19]. Alternatively, defective catecholamine synthesis due to the absence of tyrosine hydroxylase may be the underlying cause of the biochemical silent phenotype of these tumors. However, this mechanism has only been described in patients with SDHB mutations and biochemically silent abdominal sPGLs [25]. Other potential hypotheses include periodically-secreting PCs (during paroxysmal attacks) [10, 11, 14, 19] and tumors consisting of a small amount of functioning tissue due to cystic component, necrosis and/or hemorrhage [5, 11, 16, 19]. In our series, cystic and/or necrotic component on imaging comprising ≥50% of tumor was evident in 5 patients.

Biochemically silent PCs have been associated mainly with SDHB mutations [5, 14, 24]. However, this type of tumors has also been identified in other hereditary syndromes, such as Von Hippel-Lindau syndrome [3, 9], MEN2A [3], and in SDHD mutation carriers [18], as well as in apparently sporadic cases [3, 14, 19]. In accordance with the 2014 pheochromocytoma guidelines issued by the Endocrine Society [21], genetic testing was considered in our patients only in those with young age, presence of syndromic or malignant features and positive family history for any hereditary syndromes associated with PC. Only one patient fulfilled these criteria (case 4, Table 2) in whom genotyping of SDHB, VHL, RET was negative.

Overall, patients with biochemically silent PC represent a perplexing clinical scenario. Given the increased intra-operative risk of hemodynamic instability of these patients (as our study demonstrated), a pre-operative diagnosis is crucial. In cases of biochemically inactive adrenal lesions and a high index of suspicion for PC, based on imaging (unenhanced CT density >20 Hounsfield units, hyperintensity on T2-weighted MRI images, cystic changes and necrosis), functional imaging with either 123I-MIBG or 6-18F-fluorodopamine positron emission tomography scans should be considered. In these patients, pre-operative alpha-adrenergic blockade may be advisable irrespective of the presence of hypertension. Optimal target blood pressure and heart rate during treatment cannot be established given the absence of relevant evidence. However, staying in line with those proposed in the 2014 Endocrine Society guidelines [21] for the secreting PCs seems prudent.

Limitations of our study include its retrospective design (although prospective studies on this topic may not be practically feasible given the rarity of biochemically silent PCs), the small sample size which did not allow statistical analysis of our findings and that pre-operative 3-MT determination was not performed in our patients because it was not included in our diagnostic protocol of PCs/PGLs. The strength of our study is the systematic evaluation of pre-, intra- and post-operative management, complications and outcomes of patients with these tumors.

In conclusion, our study has systematically assessed for the first time the characteristics of patients with biochemically silent PCs and showed that they carry a substantial risk of hypertension, hypotension and cardiac events during adrenal surgery. Our findings underline the importance of a pre-operative diagnosis of these rare tumors and the need for such patients to be managed by endocrine, anesthesiology and adrenal surgery teams specialized and experienced on the management of patients with PCs. Further studies are needed in order to elucidate the pathophysiology of biochemically silent PCs and to identify potential predictive factors of intra-operative hemodynamic complications that will facilitate the development of valuable evidence-based management protocols.