Cardiovascular Complications in Pheochromocytoma and Paraganglioma: Does Phenotype Matter?

BACKGROUND: Adrenaline-producing tumors are mostly characterized by a sudden release of catecholamines with episodic symptoms. Noradrenergic ones are usually less symptomatic and characterized by a continuous overproduction of catecholamines that are released into the bloodstream. Their effects on the cardiovascular system can thus be different. The aim of this study was to determine the prevalence of cardiovascular complications by catecholamine phenotype. METHODS: We retrospectively analyzed data on the prevalence of cardiovascular events in 341 consecutive patients with pheochromocytoma and paraganglioma treated from 1995 to 2023. Biochemical catecholamine phenotype was determined based on plasma or urinary catecholamines and metanephrines. RESULTS: According to the phenotype, 153 patients had noradrenergic pheochromocytoma and paraganglioma and 188 had adrenergic pheochromocytoma and paraganglioma. In the whole sample, the incidence of serious cardiovascular complications was 28% (95 patients), with no difference between the phenotypes or sexes. The noradrenergic phenotype had significantly more atherosclerotic complications (composite end point of type 1 myocardial infarction and symptomatic peripheral artery disease; odds ratio, 3.58 [95% CI, 1.59-8.83]; P=0.003), while the adrenergic phenotype more often had type 2 myocardial infarction and takotsubo-like cardiomyopathy (OR, 0.24 [95% CI, 0.09-0.57]; P=0.002). These changes remained even after adjustment for conventional risk factors of atherosclerosis. CONCLUSIONS: We found a 28% incidence of cardiovascular complications in a consecutive group of patients with pheochromocytoma and paraganglioma. Patients presenting with a noradrenergic phenotype have a higher incidence of atherosclerotic complications, while the adrenergic phenotype is associated with a higher incidence of acute myocardial damage due to takotsubo-like cardiomyopathy.

Hypermetabolism and Substrate Utilization Rates in Pheochromocytoma and Functional Paraganglioma.

The overproduction of catecholamines in pheochromocytoma/paraganglioma (PPGL) induces a hypermetabolic state. The aim of this study was to evaluate the incidence of a hypermetabolic state and differences in substrate metabolism in consecutive PPGL patients divided by catecholamine phenotype. Resting energy expenditure (REE) and respiratory quotient (RQ) were measured in 108 consecutive PPGL patients and 70 controls by indirect calorimetry. Hypermetabolic state was defined according to the Mifflin St. Jeor Equation as a ratio above 110%. Hypermetabolic state was confirmed in 70% of PPGL patients, regardless of phenotype. Older age, prevalence of diabetes mellitus and arterial hypertension were correlated with hypermetabolic PPGL as compared to normometabolic form. Analysis according to overproduced catecholamine showed differences in VCO2 (p < 0.05) and RQ (p < 0.01) and thus different substate metabolism between phenotypes in hypermetabolic form of PPGL. Lipid utilization was higher in the adrenergic phenotype (p = 0.001) and positively associated with the percentage of REE ratio (R = 0.48, p < 0.001), whereas the noradrenergic phenotype preferentially oxidizes carbohydrates (P = 0.001) and is correlated with the percentage of REE ratio (R = 0.60, p < 0.001). Hypermetabolic state in PPGL is a common finding in both catecholamine phenotypes. Hypermetabolic PPGL patients are older and suffer more from diabetes mellitus and arterial hypertension. Under basal conditions, the noradrenergic type preferentially metabolizes carbohydrates, whereas the adrenergic phenotype preferentially metabolizes lipids.

Gene Profile of Adipose Tissue of Patients with Pheochromocytoma/Paraganglioma.

Background: Brown adipose tissue (BAT) is a therapeutic target to combat obesity and related disorders. Pheochromocytoma and functional paraganglioma (PPGL) are associated with activated BAT due to catecholamine excess. Our aim was to evaluate BAT activity by gene profile and assess its relation to clinical characteristics and overproduced catecholamine. Methods: mRNA expression of 15 genes in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) was measured via RT-PCR in 25 patients with PPGL and 14 controls undergoing cholecystectomy. Results: We found in VAT of PPGL higher expression of UCP1 (p < 0.001), CEBPB, PPARGC1A (both p < 0.001), PRDM16 (p = 0.069) and DIO2 (p = 0.005). UCP1 expression correlated only with norepinephrine levels and its metabolite. UCP1 expression, among others, correlated negatively with BMI, age and positively with HDLc levels. Dominance of BAT or BeAT markers was not assessed in PPGL. In SAT of PPGL, we found higher expression of ADRB3, CIDEA (both p < 0.05), and PPARGC1A (p = 0.001), but not UCP1. Conclusion: We demonstrate signs of UCP1-dependent norepinephrine-induced thermogenesis connected with higher expression of DIO2, PPARGC1A, CEBPB and PRDM16 in retroperitoneal VAT of PPGL and its relations to circulating HDLc and triglycerides levels. However, no direct relationship with increased basal energy metabolism measured by calorimetry was found.

Postoperative adrenal insufficiency in Conn's syndrome-does it occur frequently?

Primary aldosteronism (PA) is the most frequent form of endocrine hypertension. Recently, frequent clinically significant adrenal insufficiency after adrenalectomy in subjects with PA has been reported, which may make the early postsurgical management difficult. We retrospectively searched for possible adrenal insufficiency in subjects who underwent adrenalectomy for PA and have measured cortisol in the early postoperative course. We included subjects with confirmed diagnosis of PA who underwent either posture testing (blood draw at 06:00 and 08:00) and/or adrenal venous sampling (AVS) (blood draw between 08:00 and 09:00) and have also measured cortisol after surgery (cortisol measured approximately at 07:00). Cortisol was measured by immunoassay. In this study, we identified 150 subjects (age 48.5 ± 10.3 years) with available cortisol values in the early postoperative course (median [25th percentile, 75th percentile]) 6 [5,6] days. Postoperative cortisol values (551 ± 148 nmol/l) were normal and significantly higher, compared to preoperative standing cortisol values (404 ± 150 nmol/l; (P < 0.001) and AVS cortisol values (493 ± 198 nmol/l; P = 0.009), and did not significantly differ from preoperative supine cortisol values. Postsurgical cortisol values were not different among subjects with or without abnormal dexamethasone suppression test or elevated urinary free cortisol pre-surgery, and were significantly higher in subjects with abnormal diurnal cortisol variability compared with subjects with normal diurnal variability. No patient presented with adrenocortical crisis in the later follow-up. In conclusion, postoperative cortisol values did not indicate any suspicion of possible adrenal insufficiency. To exclude possible adrenal insufficiency, it may be sufficient to measure morning cortisol in the early postoperative course.

Effect of adrenalectomy on remission of subclinical left ventricular dysfunction in patients with pheochromocytoma: a speckle-tracking echocardiography study.

BACKGROUND: Pheochromocytomas (PHEO) are tumours with the ability to produce, metabolize and secrete catecholamines. Catecholamines overproduction leads to the decrease of longitudinal function of the left ventricle (LV) measured by speckle-tracking echocardiography. Patients with PHEO have a lower magnitude of global longitudinal strain (GLS) than patients with essential hypertension. GLS normalization is expected after resolution of catecholamine overproduction. METHODS: Twenty-four patients (14 females and 10 males) with a recent diagnosis of PHEO have been examined before and 1 year after adrenalectomy. An echocardiographic examination including speckle-tracking analysis with the evaluation of GLS and regional longitudinal strain (LS) in defined groups of LV segments (basal, mid-ventricular and apical) was performed. RESULTS: One year after adrenalectomy, the magnitude of GLS increased (-14.3 ± 1.8 to -17.7 ± 1.6%; P < 0.001). When evaluating the regional LS, the most significant increase in the differences was evident in the apical segment compared to mid-ventricular and basal segments of LV (-5.4 ± 5.0 vs -1.9 ± 2.7 vs -1.6 ± 3.8; P < 0.01). CONCLUSIONS: In patients with PHEO, adrenalectomy leads to an improvement of subclinical LV dysfunction represented by the increasing magnitude of GLS, which is the most noticeable in apical segments of LV.

Optimal Surgical Outcome of Minimally Invasive Partial Nephrectomy (MIPN) Based on an Early Postoperative Estimated Glomerular Filtration Rate (eGFR).

PURPOSE OF REVIEW: To compare laparoscopic partial nephrectomy (LPN) and robot-assisted partial nephrectomy (RAPN) performed in two European tertiary centers using the classic optimal surgical definition - "MIC" - and a new optimal surgical definition: the "Novel TRIFECTA" (NT) concept. We sought to strengthen the PN evidence and to test the NT's performance. RECENT FINDINGS: The study population comprehended 505 cases of localized kidney cancer from two tertiary centers between 2012 and 2019. The NT achievement was higher in the RAPN group when compared to LPN (70.5 vs. 87.4%; p = 0.004), while no differences were found when considering the MIC criteria. Also, a similar high-grade complications rate (Clavien-Dindo > III) and operative time (105 min vs. 100 min; p = NS) were found. In the multivariable regression, the RAPN approach was a predictor of NT achievement (OR 2.45; p = 0.008). NT achievement was higher in the RAPN group, while similar results were found when evaluating the MIC criteria. The NT definition could be more sensitive to the individual-specific responses related to the PN.

Pheochromocytoma With Adrenergic Biochemical Phenotype Shows Decreased GLP-1 Secretion and Impaired Glucose Tolerance.

CONTEXT: Impaired glucose homeostasis is a common finding in pheochromocytoma (PHEO), especially with adrenergic phenotype. The possible contribution of incretin dysfunction to dysglycemia in PHEO patients has not been studied. OBJECTIVE: To compare changes in pancreatic endocrine function and gut hormones' production during a liquid meal test before and 1 year after adrenalectomy. METHODS: In a prospective study, we included 18 patients with PHEO (13 females) with adrenergic biochemical phenotype. A liquid meal test with predefined isocaloric enteral nutrition was performed to evaluate dynamic changes in pancreatic hormones and incretins. RESULTS: During the meal test, insulin levels were significantly lower before adrenalectomy only in the early phase of insulin secretion, but changes in area under the curve (AUC) did not reach statistical significance (AUC = 0.07). Plasma glucagon (AUC < 0.01) and pancreatic polypeptide levels (AUC < 0.01) were suppressed in comparison with the postoperative state. Impaired response to the meal was found preoperatively for glucagon-like peptide-1 (GLP-1; AUC P < 0.05), but not glucose-dependent insulinotropic polypepide (GIP; AUC P = 0.21). No significant changes in insulin resistance indices were found, except for the homeostatic model assessment-beta index, an indicator of the function of islet ß cells, which negatively correlated with plasma metanephrine (R = -0.66, P < 0.01). CONCLUSIONS: Our study shows suppression of pancreatic α and ß cell function and impaired GLP-1 secretion during a dynamic meal test in patients with PHEO, which is improved after its surgical treatment. These data demonstrate a novel and potentially significant interconnection between excessive catecholamine production and the secretion of glucoregulatory hormones.

Blood Pressure Profile, Catecholamine Phenotype, and Target Organ Damage in Pheochromocytoma/Paraganglioma.

CONTEXT: Impaired diurnal blood pressure (BP) variability is related to higher cardiovascular risk. OBJECTIVE: To assess diurnal variability of BP and its relation to target organ damage (TOD) and catecholamine phenotype in a consecutive sample of pheochromocytoma/paraganglioma (PPGL). DESIGN: We included 179 patients with PPGL All patients underwent 24 hours of ambulatory BP monitoring to determine dipping status. Differences in plasma metanephrine or urine adrenaline were used to distinguish catecholamine biochemical phenotype. To evaluate TOD, renal functions, presence of left ventricle hypertrophy (LVH), and the subgroup (n = 111) carotid-femoral pulse wave velocity (PWV) were assessed. Structural equation modeling was used to find the relationship among nocturnal dipping, catecholamine phenotype, and TOD parameters. RESULTS: According to the nocturnal dipping, patients were divided into the three groups: dippers (28%), nondippers (40%), and reverse dippers (32%). Reverse dippers were older (P < 0.05), with a higher proportion of noradrenergic (NA) phenotype (P < 0.05), a higher prevalence of diabetes mellitus (P < 0.05), and sustained arterial hypertension (P < 0.01) and its duration (P < 0.05), as opposed to the other groups. All parameters of TOD were more pronounced only in reverse dippers compared with nondippers and dippers. The presence of NA phenotype (=absence of adrenaline production) was associated with reverse dipping and TOD (LVH and PWV). CONCLUSIONS: Patients with reverse dipping had more substantial TOD compared with other groups. The NA phenotype plays an important role, not only in impaired diurnal BP variability but also independently from dipping status in more pronounced TOD of heart and vessels.

Chromogranin A in the Laboratory Diagnosis of Pheochromocytoma and Paraganglioma.

This work discusses the clinical performance of chromogranin A (CGA), a commonly measured marker in neuroendocrine neoplasms, for the diagnosis of pheochromocytoma/paraganglioma (PPGL). Plasma CGA (cut-off value 150 µg/L) was determined by an immunoradiometric assay. Free metanephrine (cut-off value 100 ng/L) and normetanephrine (cut-off value 170 ng/L) were determined by radioimmunoassay. Blood samples were collected from PPGL patients preoperatively, one week, six months, one year and two years after adrenal gland surgery. The control patients not diagnosed with PPGL suffered from adrenal problems or from MEN2 and thyroid carcinoma. The clinical sensitivity in the PPGL group of patients (n = 71) based on CGA is 90% and is below the clinical sensitivity determined by metanephrines (97%). The clinical specificity based on all plasma CGA values after surgery (n = 98) is 99% and is the same for metanephrines assays. The clinical specificity of CGA in the control group (n = 85) was 92% or 99% using metanephrines tests. We can conclude that plasma CGA can serve as an appropriate complement to metanephrines assays in laboratory diagnosis of PPGL patients. CGA is elevated in PPGLs, as well as in other neuroendocrine or non-neuroendocrine neoplasia and under clinical conditions increasing adrenergic activity.

FGF21 Levels in Pheochromocytoma/Functional Paraganglioma.

Fibroblast growth factor 21 (FGF21) is a hepatokine with beneficial effects on metabolism. Our aim was to evaluate the relationship between the serum FGF21, and energy and glucose metabolism in 40 patients with pheochromocytoma/functional paraganglioma (PPGL), in comparison with 21 obese patients and 26 lean healthy controls. 27 patients with PPGL were examined one year after tumor removal. Basic anthropometric and biochemical measurements were done. Energy metabolism was measured by indirect calorimetry (Vmax-Encore 29N). FGF21 was measured by ELISA. FGF21 was higher in PPGL than in controls (174.2 (283) pg/mL vs. 107.9 (116) pg/mL; p < 0.001) and comparable with obese (174.2 (283) pg/mL vs. 160.4 (180); p = NS). After tumor removal, FGF21 decreased (176.4 (284) pg/mL vs. 131.3 (225) pg/mL; p < 0.001). Higher levels of FGF21 were expressed, particularly in patients with diabetes. FGF21 positively correlated in PPGL with age (p = 0.005), BMI (p = 0.028), glycemia (p = 0.002), and glycated hemoglobin (p = 0.014). In conclusion, long-term catecholamine overproduction in PPGL leads to the elevation in serum FGF21, especially in patients with secondary diabetes. FGF21 levels were comparable between obese and PPGL patients, despite different anthropometric indices. We did not find a relationship between FGF21 and hypermetabolism in PPGL. Tumor removal led to the normalization of FGF21 and the other metabolic abnormalities.

Long-Term Effect of Adrenalectomy on Cardiovascular Remodeling in Patients With Pheochromocytoma.

Context: Catecholamines may contribute to the accumulation of collagen fibers and extracellular matrix in the arterial and myocardial wall due to various mechanisms. Reversibility of this process has not been studied on both structures simultaneously. Objective: To clarify the long-term effect of excess normalization of catecholamines on carotid and myocardial wall changes in patients with pheochromocytoma or functional paraganglioma (PHEO) after tumor removal. Design, Settings, and Patients: Carotid intima-media thickness (IMT) and the left ventricular (LV) mass index were studied in 50 patients with PHEO before tumor removal and 5 years after tumor removal, and in 50 blood pressure- and age-matched essential hypertensive patients before follow-up and after 5 years of follow-up. Main Outcome Measures: Common carotid artery (CCA)-IMT and LV mass indexed to lean body mass (LBM). Results: Elimination of catecholamine excess in the PHEO group resulted in a significant decrease in CCA-IMT and LV mass index from 0.86 ± 0.17 to 0.83 ± 0.18 mm (P < 0.05) and from 3.2 ± 0.9 to 2.9 ± 0.9 g/LBM (P < 0.001), respectively. In contrast, CCA-IMT and LV mass index increased significantly from 0.78 ± 0.14 to 0.81 ± 0.15 mm (P < 0.05) and from 3.1 ± 0.7 to 3.2 ± 0.6 g/LBM (P < 0.05), respectively, in patients with essential hypertension. Conclusion: In patients with PHEO, carotid IMT and LV mass index can significantly regress after tumor removal, in contrast to the impairment of these parameters in essential hypertensive patients during the same long-term period.

Long-term effect of specific treatment of primary aldosteronism on carotid intima-media thickness.

BACKGROUND: Aldosterone has been shown to substantially contribute to the accumulation of different types of collagen fibres and growth factors in the arterial wall, thus increasing wall thickness. A previous study showed reduction of increased common carotid intima-media thickness (IMT) in patients with primary aldosteronism 1 year after adrenalectomy. Our study in patients with primary aldosteronism was aimed at comparing the long-term effect of adrenalectomy vs. spironolactone therapy on common carotid IMT regression. METHOD: Forty-two patients with confirmed primary aldosteronism (21 with aldosterone-producing adenoma treated by unilateral laparoscopic adrenalectomy, 21 treated with spironolactone) were investigated by carotid ultrasound at baseline and 1 and 6 years after the specific treatment. RESULTS: There was a decrease in common carotid IMT from 0.956 ±â€Š0.140 to 0.900 ±â€Š0.127 mm (-5.9%; P < 0.05) at 1 year and to 0.866 ±â€Š0.130 mm (-9.4%; P < 0.01) at 6 years after adrenalectomy; in the spironolactone group, common carotid IMT decreased from 0.917 ±â€Š0.151 to 0.900 ±â€Š0.165 mm (-1.8%; NS) at 1 year and to 0.854 ±â€Š0.176 mm (-6.8%; P < 0.01) at 6 years of treatment. The magnitude of improvement at 1 year was significantly higher (by 70%; P < 0.05) in the adrenalectomy group; however, the difference (by 27%) became nonsignificant at 6 years. Comparing the adrenalectomy and spironolactone groups, there was no significant difference in blood pressure decrease after treatment. CONCLUSION: In the long term, spironolactone therapy in patients with primary aldosteronism had significant effect on regression of IMT, which was comparable to surgical treatment in patients with unilateral forms of primary aldosteronism.

Adrenocortical adenoma with rhabdoid features.

We report a case of an aldosterone producing adrenocortical adenoma with rhabdoid features in a 16-year-old girl. Grossly, the tumor measured 30 mm in diameter and weighed 24 g. Histologically, the tumor was composed of approximately equal parts of tumor cells with rhabdoid features arranged in a solid and trabecular pattern and cells characterized by compact eosinophilic cytoplasm, solid growth with focal necroses, and increased mitotic activity. The lipid-rich tumor cells with ample clear vacuolized cytoplasm represent a minor component. Immunohistochemically, all the tumor cells showed the same results and were positive for vimentin, synaptophysin, Melan A, and alpha-inhibin. Cytokeratin CAM 5.2 was positive only focally. Chromogranin A, actin, alpha-actin, S100 protein, EMA, and cytokeratin AE1/AE3 were negative. Rhabdoid features have been described in many tumors of variable histogenesis; however, to the best of our knowledge, the presence of rhabdoid phenotype has never been described in either adrenocortical adenoma or carcinoma.

Lymphatic sparing laparoscopic varicocelectomy: a microsurgical repair.

PURPOSE: The division of lymphatic vessels during pediatric varicocelectomy is complicated by hydrocele formation, testicular hypertrophy due to intratesticular edema and decline in testicular function. To prevent these complications, we introduced a microsurgical lymphatic sparing dissection into laparoscopic varicocelectomy. MATERIALS AND METHODS: We retrospectively compared outcomes in 104 boys who underwent microsurgical laparoscopic repair for grade II to III varicocele between April 1999 and December 2002 to a group of 67 boys operated on using conventional laparoscopy without lymphatic preservation between January 1997 and March 1999. Using 10x to 20x optical magnification, the lymphatic vessels were identified as colorless tubular structures that were easily separated and preserved. RESULTS: After a mean followup of 17 months there was no significant difference in varicocele recurrence between the 2 groups (6.7% vs 8.9%, p = 0.56). Hydrocele formation and testicular hypertrophy occurred significantly less frequently after microsurgical repair (1.9% and 2.9%, respectively, vs 17.9% and 20.1% in the conventional group, p = 0.0003). No major complications were encountered. CONCLUSIONS: Preservation of lymphatics in laparoscopic varicocelectomy is technically feasible, and decreases hydrocele formation and the development of testicular hypertrophy. This microsurgical modification is a safe and efficacious alternative for urologists skilled in reconstructive laparoscopy.

Pseudoglandular myxoid adenoma of the adrenal gland.

Myxoid tumors of the adrenal cortex are rare. To the best of our knowledge, only 17 cases have been reported to date, including 10 carcinomas and 7 adenomas. The myxoid areas of these tumors are often evident grossly, and their extent is variable. We report on a case of a myxoid adenoma of the right adrenal gland in a 45-year-old male with a prominent pseudoglandular arrangement in more than 90% of the tumor mass, and with a minor component represented by anastomosing cords of tumor cells floating in pools of myxoid material. In addition, after extensive examination, we found foci of typical adrenocortical adenoma. Grossly, the tumor was yellowish without discernable gelatinous changes. Most of the tumor cells had a moderate amount of clear vacuolated cytoplasm and contained numerous oil-red-O-positive lipid droplets. Extracellularly, in the lumens of pseudoglands and on the background, we noticed myxoid material that stained positively with Alcian blue (pH 2.5) and weakly positively with mucicarmine and the PAS method. Immunohistochemical examination showed positivity of the tumor cells for vimentin and cytokeratin CAM5.2. Synaptophysin was weakly positive only focally. Cytokeratin AE1/AE3, EMA, and CEA were negative.

Division of lymphatic vessels at varicocelectomy leads to testicular oedema and decline in testicular function according to the LH-RH analogue stimulation test.

OBJECTIVES: To study the andrological outcome of the division of testicular lymphatic vessels at varicocelectomy in children and adolescents. METHODS: Testicular size and basal and stimulated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) values were determined prospectively in 86 patients with left unilateral varicocele grades II-III. 22 patients underwent lymphatic non-sparing surgery (LNS group), 10 of them with artery sparing (LNS/AS) and 12 without artery sparing (LNS/ANS), 23 patients underwent lymphatic sparing repair (LS group) and 41 patients were treated conservatively (NT group). RESULTS: The LNS group demonstrated significantly greater left testicular enlargement at six weeks and one year following repair, left testicular hypertrophy developed in 31.8% and hydrocele in 22.7% of patients. Marked oedema of intertubular tissue and a varying degree of tubular injury was observed in boys surgically treated for hydrocele. In the LS group, neither hypertrophy nor hydrocele developed postoperatively, the LH stimulated values were lower than in LNS/ANS group (p<0.05) and the NT group (p<0.04), the FSH stimulated values were lower than in the LNS/ANS group (p<0.001). CONCLUSIONS: Division of lymphatic vessels at varicocelectomy is associated with an excessive increase in testicular volume due to oedema, and with a reduced testicular function according to higher LH and FSH stimulated values. Preservation of lymphatics is strongly advised in varicocelectomy in adolescents to ensure better andrological outcome.