Health

Department of Endocrinology, The Royal Victoria Infirmary, Newcastle Hospitals NHS Foundation Trust, Newcastle upon-Tyne, United Kingdom

Introduction

Pheochromocytomas/paragangliomas (PHAEO/PG) are chromaffin cell tumors, which can present sporadically or as part of other familial syndromes including Hereditary Paraganglioma syndromes (HPG), multiple endocrine neoplasia 2 (MEN-2), Von Hippel-Lindau syndrome (VHL) and Neurofibromatosis type 1(NF-1). PHAEO/PG are found in about 0.2% of the patients with hypertension (1) and in 5% of all cases of adrenal incidentalomas (2, 3). The vast majority of PHAEO/PG produce catecholamines, which are metabolised into metanephrines and 3-MT (methoxytyramine). PHAEO/PG are treated with surgical resection followed by lifelong biochemical and radiological screening, especially in those patients at high risk of recurrent and/or metastatic disease (4).

Although, these tumors can occur at any age, they are more prevalent during the fourth to fifth decades (5) with a diverse clinical presentation, which can range from being asymptomatically discovered (incidental) to the typical attacks of paroxysmal headache, sweating, palpitations/tachycardia (6, 1) and may also present with fatal complications. Indeed, many patients do not have the classic triad of symptoms (7, 8) and around 5-15% can be normotensive (6, 9, 10)

NF-1 is an autosomal dominant neuro-cutaneous disorder with an estimated birth incidence of 1 in every 2500-3000 individuals (11). The clinical criteria are robust (12) and by using RNA-based assays, mutations in the NF1 can be detected in >95% of those meeting the clinical criteria (13)

While, it is recommended to screen for PHAEO/PG in individuals with other predisposing genetic disorders, neither adult nor paediatric NF-1 guidelines recommend routine biochemical screening in NF-1 patients unless patients are hypertensive or symptomatic (14, 15). Patients with undiagnosed PHAEO/PG are at risk of developing life-threatening cardiovascular complications, due to pheochromocytoma crises triggered by tumor manipulation, anaesthesia, drugs, pregnancy (16) or rarely, metastatic disease. Over the last few years, there is increased attention in the literature to the potential significance and need for biochemical screening in NF-1 patients for PHAEO/PG. As asymptomatic and normotensive NF-1 patients are not suitable candidates for screening as per the currently practiced recommendations, we were interested to examine the safety and impact of such approach on NF-1 patients, who are ultimately presented with PHAEO/PG by looking into the mode of presentation and the incidence of any adverse outcomes.

Methods

Adult patients with a diagnosis of NF-1 and PHAEO/PG were identified via a retrospective search of hospital records from a tertiary referral unit in the north east of England (The Royal Victoria Infirmary - Newcastle Hospitals NHS Foundation Trust) from 1998 to 2018. Caldicott approval was obtained prior to data collection. Retrospectively collected data for all resected PHAEO/PG was obtained and matched with a computer-based search for all histologically confirmed PHAEO/PG. Using this approach, we could track those cases of NF-1 with PHAEO/PG managed at different hospitals within the region. A parallel computer search on the NF-1 register database was performed by the national complex NF-1 service based at Manchester centre of genomic medicine.

A diagnosis of NF-1 identified by the database search was confirmed by reviewing the clinical records, complying with the clinical criteria of NF-1 and/or genetic testing. The diagnosis of PHAEO/PG was based on biochemical, radiological and histological criteria. A diagnosis of hypertension was assigned to patients stated to have such a diagnosis or described as being on anti-hypertensive medications. Classical PHAEO symptoms were defined as the presence of any of the followings: headaches, palpitations and sweating (16). Review of medical records, including history and examination, was performed retrospectively looking for the presence of any classical symptoms, even in those patients where the diagnosis was found incidentally.

Currently, Liquid chromatography with tandem mass spectrometry assay for measuring plasma metanephrines is in use since 2010. Prior to this, plasma catecholamines were measured. For urinary metanephrines, liquid chromatography with electrochemical detection method is in practice, since at least the year 2002.Because of the difference in the assays, used in other hospitals across the north of England and to account for the change in the preference for the assays used over time, we unified the interpretations of the biochemical results by adopting the use of a standard score (SS) (18). The standard score can be calculated as below:

We recorded patients’ demographics, mode of clinical presentation, biochemical, radiological, histology results and the occurrence of death, metastases and any adverse complications attributed to hypertensive crisis or circulating catecholamines.

Statistical analysis

Analysis of data was carried out using the available statistical package of SPSS-24 (Statistical Packages for Social Sciences- version 24). The significance of the difference of different percentages (qualitative data) was tested by using the Pearson Chi-square test (χ2-test) with the application of Yate's correction or Fisher Exact test whenever applicable. Statistical significance was considered whenever the p-value was equal or less than 0.05.

Patients demographics

Out of 180 patients who had PHAEO/PG resection and NF-1 database of 3715 patients, we identified 27 patients with a dual diagnosis of NF-1 and PHAEO/PG (Table 1).12 patients were identified by searching the hospital records with further 15 patients were identified through the NF-1 database. All the patients had a clinical diagnosis of NF-1 before PHAEO was diagnosed except for one patient in whom genetic testing after PHAEO resection confirmed a pathological NF-1 mutation. Two patients were siblings. The mean age at presentation with PHAEO was 43.1±12.7 years (22-65) and 77.8% (n=21) were females.

Mode of presentation:

The mode of presentation was incidental (tumours were identified by imaging performed for other indications) in 48 % (n=13); 29.6 % (n=8) and 22.2 %(n=6) presented with symptoms and during investigations for secondary hypertension, respectively. Typical PHAEO symptoms were found in 55.5 % (n=15) of patients and 52 % (n=14) were hypertensive prior to PHAEO/PG diagnosis. No patient had undergone through biochemical screening for PHAEO/PG before the later diagnosis was evident.

Diagnosis confirmation:

Imaging confirmed the presence of a unilateral adrenal mass in 77 % (n=21), a bilateral adrenal mass in 11 % (n=3), and an extra-adrenal location in 11% (n=3). Mean tumour size was 5.0±2.8 cm (1.0-13.5). All the patients had plasma and/or urinary catecholamines elevated with mean SS for plasma metanephrines (n=20) of 6.6±7.6 (0-36), plasma normetanephrines (n=20) 7.5±7.8 (0-25.6), urinary metanephrines (n=7) 7.5±7.8 (0-25.6) and urinary normetanephrines (n=6) 6.1±9.7 (0.21-25.7) . Histology results were available for 23 patients. Adrenal PHAEO was confirmed in 21 patients (of which 2 patients had composite pheochromocytoma-ganglioneuroma). Paraganglioma was confirmed histologically in 2 patients. Another patient with a pelvic neurofibroma was assumed to have intra-fibroma PG tissue as catecholamines levels normalised after neurofibroma resection. All the patients received medical therapy with an appropriate alpha-blockade agent prior to consideration of surgery.

Complications

Potentially avoidable complications had occurred in 8/23 of patients at the time of diagnosis of PHAEO/PG (Table 2). Among patients with documented complications, 4/8 were hypertensive and 5/8 presented with classical PHAEO/PG related symptoms. Three patients were found to have Ta kotsubo cardiomyopathy including one patient who presented in acute heart failure and acute lower limb ischemia due to left ventricular thrombus formation needing embolectomy. Two patients had metastatic disease; one patient received surgical resection followed by chemotherapy, while the other patient had radionuclide therapy but died shortly after that. Two patients had disease recurrence. Another patient died a result of post adrenalectomy stroke and two young females suffered hypertensive crises in pregnancy / after delivery. As compared to patients, who did not present with complications, there was no significant statistical difference in age (p= 0.389), sex (p= 0.214), tumour size (p=0.863), presence of hypertension (p=0.645), presence of typical PHAEO symptoms (p=0.879) and catecholamines levels (p=0.498).

Discussion

The prevalence of PHAEO/PG in patients with NF-1 remains debatable. While the mostly cited prevalence in the literature is 0.1-5.7% based on a retrospective review in 1999 of families with NF1(19), subsequent studies showed that the prevalence might be higher if patients were screened prospectively. In a prospective study of 156 patients with NF-1, the prevalence of PHEO / PG in NF-1 was 7.7% (20). An even higher prevalence (14.6%) was reported, when 48 consecutive NF1 patients were screened prospectively (21). This indicates that, the association between NF-1 and PHAEO/PG could have been underestimated in the past.

Mode of Presentation

In the last few years, an increase in the number of PHAEO / PG detected incidentally was evident in patients who are normotensive and asymptomatic given the widespread use of advanced imaging modalities and a better understanding of the genetic basis of the disease (2,3,18,22,23). In our cohort, PHAEO/PG was discovered incidentally in 48% of NF-1 subjects with a significant percentage of patients diagnosed in the absence of classical symptoms or elevated blood pressure.

While sustained and/or paroxysmal hypertension is a feature of PHAEO in 80-90% of affected individuals, 5-15 % of patients could be normotensive at diagnosis (24). Even with increased circulating catecholamines levels, blood pressure may not be elevated due to multiple factors including catecholamines-induced hypovolemia due to vasoconstriction, the rate of catecholamines inactivation and availability to target cells, the reactivity of vascular smooth muscle and catecholamines receptor numbers and sensitivity (25). It has been found that, chronic exposure to a high level of catecholamines may result in desensitisation of the postjunctional α1- and α 2-adrenergic receptor causing an attenuation to their vasopressor responses (26). In our series, 14/27 (52 %) of patients were not known to be hypertensive before the diagnosis of PHAEO/PG.

The classical triad of paroxysmal headache, palpitations, and sweating is strongly associated with catecholamines excess and often described as “an attack” (17). However, the disease is still referred to as “the great mimic” as the clinical presentation can be diverse with non-specific signs and symptoms (27). In our series, 15/27 (55.5 %) of patients presented with at least one of the classical symptoms while the remaining patients presented with a variety of other symptoms (Table 1)

Adverse clinical outcomes

In our series, potentially avoidable complications were evident in 8/27 (35 %) of patients (Table 2). The spectrum of such outcomes ranged from moderate-severe crises to metastases and deaths. One patient presented with a fall and multiple fractures which on further evaluation revealed a metastatic PHAEO to the bones and was deceased soon after the diagnosis was made.

In one patient there was a 7-years history of anxiety, low mood, and chest pain. The patient received a diagnosis of non-ST elevation myocardial infarction and treated with dual antiplatelet therapy and ß receptors blockers for 1 year before subsequent cardiac catheterisation and MRI showed no evidence of ischemic heart disease. Indeed, the delay in recognizing PHAEO in this patient resulted in exposure to the risks of an invasive cardiac procedure as well as the risk of worsening hypertension and bleeding due to the use of ß blockers and dual antiplatelet therapy.

Review of the literature

Several studies in the literature have reported heterogeneity in the presentation of PHAEO/PG in NF-1 (Table 3) and questioned the significance of screening. In a large retrospective study of PHAEO/PG in NF-1 population (18), Gruber et al studied 41 patients from the Mayo clinic database between 1959 to 2015 and found that the diagnosis of PHAEO/PG was mostly incidental over the last 2 decades with only three patients (7.3%) who were found through biochemical case detection . Moreover, the authors observed that, all cases of bilateral, recurrent and metastatic diseases occurred in women. In their study, the authors recommended biochemical screening for PHAEO/PG in all the patients with NF-1 at an early age (age 10-14) with a repeat evaluation every 3 years and before elective surgical interventions and conception.

In another study, Kebenkian et. al. (20) prospectively screened 156 patients with NF-1 using a combination of urinary metanephrines and abdominal imaging and subsequently found 12 cases of PHAEO/PG. Without this prospective methodology, only 2 patients out of the 12, could have been diagnosed using the current approach of electing only symptomatic and hypertensive patients for screening. In this study, the authors suggested, initiating screening every 4–5 years after 40 years of age.

Furthermore, significant adverse outcomes were described in the cohort of NF-1 patients who ultimately found to have PHAEO/PG. Petr EJ et al (32) recently studied 17 patients with NF-1/PHAEO/PG; two patients were found to have metastatic disease and six suffered cardiovascular crises, especially during surgical procedures and/or delivery. Buttz et al. (33) investigated the peri-operative outcomes of PHAEO/PG resection at the Mayo clinic cohort from 2000-2016 and found that patients with NF-1 suffer the worse intraoperative hemodynamic course and more severe postoperative complications, as compared to other PHAEO/PG genetic syndromes. This was felt due to larger tumor size and higher levels of catecholamines as compared to other familial PHAEO/PG syndromes where more strict and timely screening is applied.

We have recently reviewed all published isolated case reports of PHAEO/PG in patients with NF-1 and found at least 73 cases (34); 36/73 did not present with any of classical symptoms while 27/73 were normotensive at the time of PHAEO/PG diagnosis. Furthermore, we found that, 31/73 of patients presented with life-threatening complications and interestingly, the majority were relatively young Our findings, in contrast to Kebenikan et al (36), would favor considering screening at an earlier age.

The current Practice

The currently practiced guidelines for the management of NF1 recommends that patients with NF-1 should have a specialist clinic visit once a year where clinical evaluation is performed and blood pressure is measured given the association with renal artery stenosis and PHAEO (14). According to the American college of medical genetics and genomics (ACMG), only hypertensive NF1 patients aged 30 years or above who are pregnant, and/ or symptomatic should be considered for biochemical or imaging screening given the lack of any randomised studies on the efficacy of biochemical or imaging screening to detect pheochromocytoma in asymptomatic patients with NF1 (35). The presumed perception of an infrequent occurrence of PHAEO / PG in NF-1 could also be another reason for the lack of an agreed consensus with regards to screening asymptomatic patients.

However, the value of screening needs to be reconsidered in light of the emerging findings from retrospective and prospective studies over the last few years. The currently perceived low risk of PHAEO/PG in NF-1 is likely to be underestimated as most of our knowledge is derived from retrospective case series with a small number of patients included, albeit higher prevalence was evident on prospective case detection (20,21). In addition, it is clear that, the current case detection strategy fails to identify those patients who are incidentally confirmed to have PHAEO/PG. Finally, our observations, in addition to the evidence provided from recent studies (28,29), suggest that NF-1 subjects are at risk of developing catastrophic sequalae upon under-recognition of PHAEO/PG.

The literature and our own findings suggest that majority of NF-1 who were ultimately found to have PHAEO/PG reported non-specific symptoms and had been through multiple consultations, extensive investigations and invasive procedures over years before the diagnosis of PHAEO/PG was reached. Besides the risk of catastrophic complications that may eventually arise, this patient pathway generates additional medical costs, hospital visits and uncertainty, which negatively impact the patients’ mental and physical wellbeing. In view of the above, it may be argued that routine screening could be safe and cost-effective in reducing the burden, morbidity and mortality in patients with NF-1. A well-designed randomised controlled trial or a population based-study is necessary to address this important question.

Limitations and strengths

Our study is retrospective and therefore the strength of evidence is relatively low. The NF-1 register may not be representative of the true prevalence of NF-1, a potential source of bias. Also, it was challenging to track all the medical records and obtain full clinical information as many patients were treated in different units across Northern England. Despite those caveats, to our knowledge, our series represents the largest European cohort of NF-1 and PHAEO/PG and one of the few to look into the adverse clinical outcomes over the last 20 years.

Conclusion

Relying on the symptoms and blood pressure status to decide if screening for PHAEO/PG is needed in NF-1 patients may be associated with unnecessary risk and avoidable harm. We recommend to measure urinary or plasma metanephrines at an early age (10-14 years) and repeat those measurements every 3 years in all patients with NF-1 regardless of the way they present. Such approach is less periodic as compared to other hereditary PHAEO/PG syndromes where frequent surveillance is needed and this can be conceptualized in light of the lower prevalence, penetrance rate and incidence of multifocal disease in NF-1 (33,35,36). Subsequent prospective studies examining and comparing the clinical outcomes of routine biochemical screening versus the current surveillance practice in the NF-1 population is warranted.

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