Phaeochromocytoma and paraganglioma (PPGL) are chromaffin cell tumours that require timely diagnosis because of their potentially serious cardiovascular and sometimes life- threatening sequelae. ...Tremendous progress in biochemical testing, imaging, genetics and pathophysiological understanding of the tumours has far-reaching implications for physicians dealing with hypertension and more importantly affected patients. Because hypertension is a classical clinical clue for PPGL, physicians involved in hypertension care are those who are often the first to consider this diagnosis. However, there have been profound changes in how PPGLs are discovered; this is often now based on incidental findings of adrenal or other masses during imaging and increasingly during surveillance based on rapidly emerging new hereditary causes of PPGL. We therefore address the relevant genetic causes of PPGLs and outline how genetic testing can be incorporated within clinical care. In addition to conventional imaging (computed tomography, MRI), new functional imaging approaches are evaluated. The novel knowledge of genotype-phenotype relationships, linking distinct genetic causes of disease to clinical behaviour and biochemical phenotype, provides the rationale for patient-tailored strategies for diagnosis, follow-up and surveillance. Most appropriate preoperative evaluation and preparation of patients are reviewed, as is minimally invasive surgery. Finally, we discuss risk factors for developing metastatic disease and how they may facilitate personalised follow-up. Experts from the European Society of Hypertension have prepared this position document that summarizes the current knowledge in epidemiology, genetics, diagnosis, treatment and surveillance of PPGL.
Recent years have seen major changes in clinical practice which may have affected the incidence rates of pheochromocytoma(PCC)/sympathetic paraganglioma(sPGL). There is, however, a lack of up-to-date ...information describing trends in these incidence rates.
We searched the Dutch pathology registry to identify all histopathologically confirmed cases of PCC/sPGL diagnosed between 1995 and 2015. We calculated incidence rates according to age category as well as age-standardized incidence rates (ASR). We also searched Medline and Embase to find data on nationwide incidence rates of PCC/sPGL.
The nationwide pathology study revealed a total of 1493 patients with either PCC or sPGL. The ASR for PCC increased from 0.29 (95% CI: 0.24–0.33) to 0.46 (95% CI: 0.39–0.53) per 100,000 person-years in the periods 1995–1999 and 2011–2015, respectively. For sPGL the ASR in these same periods were 0.08 (95% CI: 0.06–0.10) and 0.11 (95% CI: 0.09–0.13) per 100,000 person-years, respectively. Concomitantly, PCC size decreased (β −0.17; P < .001) and age at diagnosis increased (β 0.13; P = .001). Our systematic search yielded 3 papers reporting on a total of 530 PCC/sPGL cases, showing a combined annual incidence rate varying from 0.04 to 0.21 per 100,000 person-years.
Incidence rates of PCC/sPGL have increased significantly over the past two decades. This trend coincides with a higher age and a smaller tumor size at diagnosis. Most likely these observations are at least in part the result of changes in clinical practice during the study period, with a more intensified use of both imaging studies and biochemical tests for detecting PCC/sPGL.
•Up-to-date epidemiological data on PCC/sPGL are lacking.•The incidence rate of PCC/sPGL has increased significantly during the past two decades.•This rise in incidence rate is accompanied by a reduction in tumor size and a higher age at diagnosis.•The observed epidemiological changes are most likely the result of more intensified use of better diagnostics.
Abstract
Context
Imaging plays an important role in the characterization of adrenal tumors, but findings might be inconclusive. The clinical question is whether 18F fluodeoxyglucose (18F-FDG) ...positron emission tomography/computed tomography (PET/CT) is of diagnostic value in this setting.
Objective
This meta-analysis was aimed at the diagnostic value of 18F-FDG PET/CT in differentiating benign from malignant adrenal tumors discovered either as adrenal incidentaloma or during staging or follow-up of oncologic patients.
Data sources
PubMed, EMBASE, Web of Science, and Cochrane Library were searched to select articles between 2000 and 2021.
Study selection
We included studies describing the diagnostic value of 18F-FDG PET/CT in adult patients with an adrenal tumor. Exclusion criteria were 10 or fewer participants, insufficient data on histopathology, clinical follow-up, or PET results. After screening of title and abstract by 2 independent reviewers, 79 studies were retrieved, of which 17 studies met the selection criteria.
Data extraction
Data extraction using a protocol and quality assessment according to QUADAS-2 was performed independently by at least 2 authors.
Data synthesis
A bivariate random-effects model was applied using R (version 3.6.2.). Pooled sensitivity and specificity of 18F-FDG PET/CT for identifying malignant adrenal tumors was 87.3% (95% CI, 82.5%-90.9%) and 84.7% (95% CI, 79.3%-88.9%), respectively. The pooled diagnostic odds ratio was 9.20 (95% CI, 5.27-16.08; P < .01). Major sources of heterogeneity (I2, 57.1% 95% CI, 27.5%-74.6%) were in population characteristics, reference standard, and interpretation criteria of imaging results.
Conclusions
18F-FDG PET/CT had good diagnostic accuracy for characterization of adrenal tumors. The literature, however, is limited, in particular regarding adrenal incidentalomas. Large prospective studies in well-defined patient populations with application of validated cutoff values are needed.
Abstract
Context
Pretreatment with α-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL).
...Objective
To determine which type of α-adrenergic receptor blocker provides the best efficacy.
Design
Randomized controlled open-label trial (PRESCRIPT; ClinicalTrials.gov NCT01379898)
Setting
Multicenter study including 9 centers in The Netherlands.
Patients
134 patients with nonmetastatic PPGL.
Intervention
Phenoxybenzamine or doxazosin starting 2 to 3 weeks before surgery using a blood pressure targeted titration schedule. Intraoperative hemodynamic management was standardized.
Main Outcome Measures
Primary efficacy endpoint was the cumulative intraoperative time outside the blood pressure target range (ie, SBP >160 mmHg or MAP <60 mmHg) expressed as a percentage of total surgical procedure time. Secondary efficacy endpoint was the value on a hemodynamic instability score.
Results
Median cumulative time outside blood pressure targets was 11.1% (interquartile range IQR: 4.3–20.6 in the phenoxybenzamine group compared to 12.2% (5.3–20.2) in the doxazosin group (P = .75, r = 0.03). The hemodynamic instability score was 38.0 (28.8–58.0) and 50.0 (35.3–63.8) in the phenoxybenzamine and doxazosin group, respectively (P = .02, r = 0.20). The 30-day cardiovascular complication rate was 8.8% and 6.9% in the phenoxybenzamine and doxazosin group, respectively (P = .68). There was no mortality after 30 days.
Conclusions
The duration of blood pressure outside the target range during resection of a PPGL was not different after preoperative treatment with either phenoxybenzamine or doxazosin. Phenoxybenzamine was more effective in preventing intraoperative hemodynamic instability, but it could not be established whether this was associated with a better clinical outcome.
Abstract Background The reported annual incidence of adrenocortical carcinoma (ACC) is 0.5–2.0 cases per million individuals. Updated population-based studies on incidence are lacking. The aim of ...this nationwide survey was to describe the incidence and survival rates of ACC in the Netherlands. Secondary objectives were to evaluate changes in both survival rates and the number of patients undergoing surgery. Methods All ACC patients registered in the Netherlands Cancer Registry (NCR) between 1993 and 2010 were included. Data on demographics, stage of disease, primary treatment modality and survival were evaluated. Results Included were 359 patients, 196 of whom were female (55%). Median age at diagnosis was 56 years (range 1–91). The 5-year age-standardised incidence rate decreased from 1.3 to 1.0 per one million person-years. Median survival for patients with stage I–II, stage III and stage IV disease was 159 months (95% confidence interval (CI) 93–225 months), 26 months (95% CI: 4–48 months) and 5 months (95% CI: 2–7 months), respectively ( P < 0.001). Improvement in survival was not observed, as reflected by the lack of association between survival and time of diagnosis. The percentage of patients receiving treatment within 6 months after diagnosis increased significantly from 76% in 1993–1998 to 88% in 2005–2010 ( P = 0.047), mainly due to an increase in surgery for stage III–IV patients. Conclusion These nationwide data provide an up-to-date survey of the epidemiology of ACC in the Netherlands. A trend towards a decreasing overall incidence rate was observed. Survival rates did not change during this period despite an increased number of surgical procedures.
Abstract
Background
Up to 7% of all adrenal incidentalomas (AIs) are pheochromocytomas (PCCs). In the evaluation of AI, it is generally recommended that PCC be excluded by measurement of plasma-free ...or 24-hour urinary fractionated metanephrines. However, recent studies suggest that biochemical exclusion of PCC not be performed for lesions with CT characteristics of an adrenocortical adenoma (ACA).
Aim
To determine the proportion of PCCs with ACA-like attenuation or contrast washout on CT.
Methods
For this multicenter retrospective study, two central investigators independently analyzed the CT reports of 533 patients with 548 histologically confirmed PCCs. Data on tumor size, unenhanced Hounsfield units (HU), absolute percentage washout (APW), and relative percentage washout (RPW) were collected in addition to clinical parameters.
Results
Among the 376 PCCs for which unenhanced attenuation data were available, 374 had an attenuation of >10 HU (99.5%). In the two exceptions (0.5%), unenhanced attenuation was exactly 10 HU, which lies just within the range of ≤10 HU that would suggest a diagnosis of ACA. Of 76 PCCs with unenhanced HU > 10 and available washout data, 22 (28.9%) had a high APW and/or RPW, suggestive of ACA.
Conclusion
Based on the lack of PCCs with an unenhanced attenuation of <10 HU and the low proportion (0.5%) of PCCs with an attenuation of 10 HU, it seems reasonable to abstain from biochemical testing for PCC in AIs with an unenhanced attenuation of ≤10 HU. The assessment of contrast washout, however, is unreliable for ruling out PCC.
This retrospective study examined the CT characteristics of 548 PCCs. The findings suggest that biochemical testing for PCC be avoided in incidentalomas with unenhanced attenuation ≤ 10 HU.
Pheochromocytomas and sympathetic paraganglioma (PPGL) are rare chromaffin cell tumors originating in the adrenal medulla and sympathetic paraganglia, respectively, which share the capacity to ...synthesize and release catecholamines. The incidence of PPGL has increased in recent years. Surgical resection is the only curative treatment for PPGL. Management of patients with PPGL is complex and should be done by a specialized multidisciplinary team in centers with broad expertise. Surgical resection of a PPGL is a high-risk procedure for which optimal pretreatment with antihypertensive drugs is required in combination with state-of-the-art surgical procedures and anesthesiological techniques. In this article we discuss the underlying evidence and the pros and cons of presurgical medical preparation. Finally, the areas of uncertainty and controversies in this field are addressed.
Pheochromocytomas and paragangliomas (PPGLs) have a heterogeneous prognosis, the basis of which remains unclear. We, therefore, assessed disease-specific survival (DSS) and potential predictors of ...progressive disease in patients with PPGLs and head/neck paragangliomas (HNPGLs) according to the presence or absence of metastases.
This retrospective study included 582 patients with PPGLs and 57 with HNPGLs. DSS was assessed according to age, location and size of tumours, recurrent/metastatic disease, genetics, plasma metanephrines and methoxytyramine.
Among all patients with PPGLs, multivariable analysis indicated that apart from older age (HR = 5.4, CI = 2.93–10.29, P < 0.0001) and presence of metastases (HR = 4.8, CI = 2.41–9.94, P < 0.0001), shorter DSS was also associated with extra-adrenal tumour location (HR = 2.6, CI = 1.32–5.23, P = 0.0007) and higher plasma methoxytyramine (HR = 1.8, CI = 1.11–2.85, P = 0.0170) and normetanephrine (HR = 1.8, CI = 1.12–2.91, P = 0.0160). Among patients with HNPGLs, those with metastases presented with longer DSS compared to patients with metastatic PPGLs (33.4 versus 20.2 years, P < 0.0001) and only plasma methoxytyramine (HR = 13, CI = 1.35–148, P = 0.0380) was an independent predictor of DSS. For patients with metastatic PPGLs, multivariable analysis revealed that apart from older age (HR = 6.2, CI = 3.20–12.20, P < 0.0001), shorter DSS was associated with the presence of synchronous metastases (HR = 4.9, CI = 2.78–8.80, P < 0.0001), higher plasma methoxytyramine (HR = 2.4, CI = 1.44–4.14, P = 0.0010) and extensive metastatic burden (HR = 2.1, CI = 1.07–3.79, P = 0.0290).
DSS among patients with PPGLs/HNPGLs relates to several presentations of the disease that may provide prognostic markers. In particular, the independent associations of higher methoxytyramine with shorter DSS in patients with HNPGLs and metastatic PPGLs suggest the utility of this biomarker to guide individualized management and follow-up strategies in affected patients.
•Assessment of DSS in one of the largest cohorts of patients with & without metastatic PPGLs.•In metastatic PPGLs, high tumour burden was an independent predictor of DSS.•In metastatic PPGLs, synchronous metastasis was an independent predictor of DSS.•In metastatic PPGLs, elevated plasma methoxytyramine was an independent predictor of DSS.•In HNPGLs, elevated plasma methoxytyramine was an independent predictor of DSS.
To assess the diagnostic accuracy of unenhanced computed tomography (CT) attenuation values to exclude a pheochromocytoma in the diagnostic work-up of patients with an adrenal incidentaloma and to ...model the associated difference in diagnostic costs.
The MEDLINE and Embase databases were searched from indexing to September 27, 2018, and studies reporting the proportion of pheochromocytomas on either side of the 10-Hounsfield unit (HU) threshold on unenhanced CT were included. The pooled proportion of pheochromocytomas with an attenuation value greater than 10 HU was determined, as were the modeled financial costs of the current and alternative diagnostic approaches.
Of 2957 studies identified, 31 were included (N=1167 pheochromocytomas). Overall risk of bias was low. Heterogeneity was not observed between studies (Q=11.5, P=.99, I
=0%). The pooled proportion of patients with attenuation values greater than 10 HU was 0.990 (95% CI, 0.984-0.995). The modeled financial costs using the new diagnostic approach were €55 (∼$63) lower per patient.
Pheochromocytomas can be reliably ruled out in the case of an adrenal lesion with an unenhanced CT attenuation value of 10 HU or less. Therefore, determination of metanephrine levels can be restricted to adrenal tumors with an unenhanced CT attenuation value greater than 10 HU. Implementing this novel diagnostic strategy is cost-saving.
Long-term follow-up has been recommended for patients with pheochromocytoma or paraganglioma (PPGL) due to potential for recurrent disease. However, the need to follow patients with sporadic PPGL has ...recently become controversial.
To investigate the prevalence of recurrence among patients with sporadic compared with hereditary PPGL and to identify predictors of recurrence for sporadic disease.
This multicenter study included retrospective data from 1127 patients with PPGL. In addition to sex and age at primary tumor diagnosis, clinical information included location, size, and catecholamine phenotype of primary tumors, genetic test results, and subsequent development of recurrent and/or metastatic disease. Patients with sporadic PPGL were defined as those with negative genetic test results.
Prevalence of recurrence among patients with sporadic PPGL (14.7%) was lower (P < 0.001) than for patients with pathogenic variants that activate pseudohypoxia pathways (47.5%), but similar to those with variants that activate kinase pathways (14.9%). Among patients with sporadic recurrent PPGL, 29.1% and 17.7% were respectively diagnosed at least 10 and 15 years after first diagnosis. Multivariable regression analysis showed that a noradrenergic/dopaminergic phenotype (HR 2.73; 95% CI, 1.553-4.802; P < 0.001), larger size (HR 1.82; 95% CI, 1.113-2.962; P = 0.017) and extra-adrenal location (HR 1.79; 95% CI, 1.002-3.187; P = 0.049) of primary tumors were independent predictors of recurrence in sporadic PPGL.
Patients with sporadic PPGL require long-term follow-up, as supported by the 14.7% prevalence of recurrent disease, including recurrences at more than 10 years after first diagnosis. The nature of follow-up could be individualized according to tumor size, location, and biochemical phenotype.
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