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Endocrine-related Cancer Jun 2024Pheochromocytoma (PCC) and abdominal paraganglioma (aPGL) (together abbreviated PPGL) frequently present with an underlying genetic event in a PPGL driver gene, and...
Pheochromocytoma (PCC) and abdominal paraganglioma (aPGL) (together abbreviated PPGL) frequently present with an underlying genetic event in a PPGL driver gene, and additional susceptibility genes are anticipated. Here we re-analysed whole-exome sequencing data for PCC patients and identified two patients with rare missense variants in the calcium voltage-gated channel subunit 1H gene (CACNA1H). CACNA1H variants were also found in the clinical setting in PCC patients using targeted sequencing and from analysis of The Cancer Genome Atlas database. In total, CACNA1H variants were found in six PCC cases. Three of these were constitutional and two are known to have functional consequences on hormone production and gene expression in primary aldosteronism and aldosterone-producing adrenocortical adenoma. In general, PPGL exhibited reduced CACNA1H mRNA expression as compared to normal adrenal. Immunohistochemistry showed strong CACNA1H (CaV3.2) staining in adrenal medulla while PPGL typically had weak or negative staining. Reduced CACNA1H gene expression was especially pronounced in PCC as compared to aPGL and in PPGL with Cluster 2 kinase signalling phenotype. Furthermore, CACNA1H levels correlated with HIF1A and HIF2A. Moreover, TCGA data revealed a correlation between CACNA1H methylation density and gene expression. Expression of rCacna1h in PC12 cells induced differential protein expression profiles determined by mass spectrometry as well as a shift in the membrane potential where maximum calcium currents were observed as determined by electrophysiology. The findings suggest the involvement of CACNA1H/CaV3.2 in pheochromocytoma development and establish a potential link between the aetiology of adrenomedullary and adrenocortical tumor development.
PubMed: 38864697
DOI: 10.1530/ERC-23-0061 -
Cureus May 2024Pheochromocytomas are tumors that develop from the chromaffin cells of the adrenal medulla. More than 40% of cases of pheochromocytomas are associated with genetic...
Pheochromocytomas are tumors that develop from the chromaffin cells of the adrenal medulla. More than 40% of cases of pheochromocytomas are associated with genetic conditions such as neurofibromatosis type 1 (NF1) or von Hippel-Lindau syndrome. Cystic pheochromocytomas are rare, generally asymptomatic, and thus of bigger size at the time of diagnosis. Surgical treatment is necessary to prevent cardiovascular morbidity and malignancy risk. We report the case of a 27-year-old patient admitted for further examination of a left adrenal mass that was discovered by an abdominal CT scan in the context of abdominal pain associated with hypertension evolving for three years. The clinical examination showed the presence of multiple café au lait spots, axillary and inguinal freckling with two dermal neurofibromas diagnosed clinically, as well as Lisch nodules on bilateral ophthalmic examination, thus meeting the clinical criteria for the diagnosis of NF1. The clinical laboratory investigation showed elevated urinary metanephrine and normetanephrine levels. CT scan examination showed a 10 cm left adrenal cystic mass on abdominal CT. This mass uptake of the radioligand in metaiodobenzylguanidine (MIBG) scintigraphy without secondary extra-adrenal localization allowed the diagnosis of a seemingly benign cystic pheochromocytoma to be made. The patient was put on presurgical drug preparation with volume expansion and then underwent left unilateral adrenalectomy. The histopathological study was in favor of a rather aggressive cystic pheochromocytoma with a pheochromocytoma of the adrenal gland scaled (PASS) score of 9. Blood pressure and urine catecholamines at seven days, three months, six months, and one year after surgery were normalized. Cystic pheochromocytoma is a rare tumor with a potentially poor prognosis. It is characterized by a more insidious evolution and a larger volume at diagnosis. It should be considered a diagnosis in patients with a cystic adrenal mass or an extra-adrenal mass with fluctuating blood pressure during surgery. This case illustrates the importance of both presurgical preparation and screening for pheochromocytoma in neurofibromatosis type 1.
PubMed: 38864044
DOI: 10.7759/cureus.60151 -
Medicina Clinica Jun 2024Pheochromocytomas are rare neuroendocrine tumors that derive from the chromaffin cells of the adrenal medulla and secrete catecholamines. The measurement of plasma or... (Review)
Review
Pheochromocytomas are rare neuroendocrine tumors that derive from the chromaffin cells of the adrenal medulla and secrete catecholamines. The measurement of plasma or fractionated urine metanephrines is the hormonal determination of choice for the biochemical diagnosis. Once the biochemical diagnosis is confirmed, the next step is the localization study. It is recommended to request a genetic study in all patients with pheochromocytomas since 40% of cases are hereditary. Once the diagnostic study is completed, preoperative treatment with alpha blockers should be instituted at least 7-14 days before adrenalectomy. However, in low-risk patients, the omission of presurgical treatment could be considered if the surgery is performed in centers with experience and a strict monitoring of the patient is carried out during the perioperative period. This document offers a practical guide on the diagnosis and perioperative approach in patients with pheochromocytomas.
PubMed: 38849272
DOI: 10.1016/j.medcli.2024.03.025 -
Cureus Apr 2024Pheochromocytomas (PCCs) and paragangliomas (PGLs) represent tumors arising from chromaffin cells of the adrenal medulla and extra-adrenal sympathetic paraganglia,...
Pheochromocytomas (PCCs) and paragangliomas (PGLs) represent tumors arising from chromaffin cells of the adrenal medulla and extra-adrenal sympathetic paraganglia, respectively. PCCs commonly produce one or more catecholamines (epinephrine, norepinephrine, and dopamine), but rarely are they biochemically silent. PGLs on the other hand, generally do not produce catecholamines. They have the highest heritability of all adrenal tumors and are known to be associated with genetic mutations. Patients with hereditary tumors typically present at a younger age and with multifocal disease when compared to sporadic disease. Specific genetic mutations have been well established with hereditary syndromes involving PCC/PGLs. Further research has aimed to identify other mutations and delineate specific phenotypes associated with these mutations. A 34-year-old woman presented for evaluation following a laparoscopic appendectomy that identified a 4-cm well-differentiated neuroendocrine tumor on final pathology. Further work-up included a repeat CT scan followed by a Dotatate PET CT scan which revealed a large (7.3 x 5.8 cm) periaortic mass related to the left adrenal gland. Functional adrenal work-up was negative and her Chromogranin A level was 679 ng/mL. She did report intermittent chest tightness and palpitations but was otherwise asymptomatic. The patient subsequently underwent an exploratory laparotomy with left adrenalectomy and adjacent tumor resection as well as completion of right hemicolectomy with ileocolonic anastomosis. Surgical pathology revealed two distinct masses consistent with multifocal PCC. No residual tumor was found in the colectomy specimen and 24 lymph nodes were negative. She had an uneventful recovery and genetic testing showed a variant of uncertain significance for the POLE and VHL genes. She has received genetic counseling and will be enrolled in an appropriate surveillance protocol.
PubMed: 38813302
DOI: 10.7759/cureus.59295 -
Scientific Reports May 2024The current study aimed to investigate the effect of Sox9-Cre-directed Nr5a1-conditional knockout (Sox9-Cre;Nr5a1) on adrenal development. We showed that SOX9 is...
The current study aimed to investigate the effect of Sox9-Cre-directed Nr5a1-conditional knockout (Sox9-Cre;Nr5a1) on adrenal development. We showed that SOX9 is expressed by adrenocortical cells at E10.5-E11.5 but is extinguished no later than E12.5. The number of adrenocortical cells significantly reduced in Sox9-Cre;Nr5a1 mice while the number of cleaved caspase 3-positive cells increased compared to that in the controls at E11.5-E12.5, when the adrenal primordium (AP) is about to expand. This indicated that fetal adrenocortical cells are lost via apoptosis due to Nr5a1 ablation by E12.5. Both medulla formation and encapsulation were perturbed, accompanied by a smaller AP size, in Sox9-Cre;Nr5a1 mice during embryonic development. Adult Sox9-Cre;Nr5a1 adrenals were hypoplastic and exhibited irregular organization of the medulla with aberrant sex differentiation in the X zone. Additionally, there were histologically eosin-negative vacuolated cells, which were negative for both the X-zone marker 20αHSD and the steroidogenesis marker 3βHSD at the innermost cortex of Sox9-Cre;Nr5a1 adrenals. Although Nr5a1 adrenals were hypoplastic, a small number of chromaffin cells were properly located in the center, having normal sex differences in the X-zone. The results collectively provided in-vivo evidence that Nr5a1 plays a critical role in AP expansion and subsequent adrenal development.
Topics: Animals; SOX9 Transcription Factor; Mice; Steroidogenic Factor 1; Adrenal Glands; Integrases; Mice, Knockout; Female; Male
PubMed: 38811798
DOI: 10.1038/s41598-024-63264-9 -
PloS One 2024Pheochromocytoma, or paraganglioma (PPGL), is a tumor that arises from catecholamine-producing chromaffin cells of the adrenal medulla or paraganglion. Systemic therapy,...
Evaluation of pharmacokinetics, safety, and efficacy of [211At] meta-astatobenzylguanidine ([211At] MABG) in patients with pheochromocytoma or paraganglioma (PPGL): A study protocol.
BACKGROUND
Pheochromocytoma, or paraganglioma (PPGL), is a tumor that arises from catecholamine-producing chromaffin cells of the adrenal medulla or paraganglion. Systemic therapy, such as the combination of cyclophosphamide, vincristine, and dacarbazine or therapeutic radiopharmaceuticals such as [131I] meta-iodobenzylguanidine (MIBG), may be administered in cases of locally advanced tumors or distant metastases. However, the current therapies are limited in terms of efficacy and implementation. [211At] meta-astatobenzylguanidine (MABG) is an alpha-emitting radionuclide-labeled ligand that has demonstrated remarkable tumor-reducing effects in preclinical studies, and is expected to have a high therapeutic effect on pheochromocytoma cells.
METHODS
We are currently conducting an investigator-initiated first-in-human clinical trial to evaluate the pharmacokinetics, safety, and efficacy of [211At] MABG. Patients with locally unresectable or metastatic PPGL refractory to standard therapy and scintigraphically positive [123I] MIBG aggregation are being recruited, and a 3 + 3 dose escalation design was adopted. The initial dose of [211At] MABG is 0.65 MBq/kg, with a dose escalation in a 1:2:4 ratio in each cohort. Dose-limiting toxicity is observed for 6 weeks after a single bolus dose of [211At] MABG, and the patients are observed for 3 months to explore safety and efficacy profiles. The primary endpoint is dose-limiting toxicity to determine both maximum tolerated and recommended doses. The secondary endpoints include radiopharmacokinetics, urinary radioactive excretion rate, urinary catecholamine response rate, objective response rate, progression free survival, [123I] MIBG scintigraphy on reducing tumor accumulation, and quality of life.
TRIALS REGISTRATION
jRCT2021220012 registered on 17 June 2022.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Adrenal Gland Neoplasms; Guanidines; Paraganglioma; Pheochromocytoma; Radiopharmaceuticals; Treatment Outcome; Clinical Trials, Phase I as Topic
PubMed: 38805424
DOI: 10.1371/journal.pone.0303623 -
Problemy Endokrinologii Oct 2023Pheochromocytoma (PHEO) is a tumor from the chromaffin tissue of the adrenal medulla, capable of hyperproduction of catecholamines. The increased production of hormones... (Comparative Study)
Comparative Study
BACKGROUND
Pheochromocytoma (PHEO) is a tumor from the chromaffin tissue of the adrenal medulla, capable of hyperproduction of catecholamines. The increased production of hormones by the tumor leads to catecholamine crises, which have a pathological effect on all organs and systems. In the primary diagnosis of pheochromocytomas, it is important to determine the level of the metabolite of catecholamines - metanephrines. Currently, in clinical practice, various methods are used to determine the level of this metabolite: in blood plasma or in urine, total or only free form, fractionated analysis or unfractionated.
AIM
Comparison of the effectiveness of various methods for determining the level of metanephrines for the diagnosis of pheochromocytomas.
MATERIALS AND METHODS
A retrospective single-center cohort study was conducted on a sample of patients who were initially operated on for adrenal neoplasm at the Pirogov St. Petersburg State University High Medical Technology Clinic from November 2007 to December 2022 and who passed analysis to determine the level of blood or urine metanephrins before surgical treatment. The results of tests for metanephrine and tumor size were evaluated.
RESULTS
1088 patients with adrenal neoplasms who underwent surgical treatment were examined, of which 348 had histologically confirmed the presence of pheochromocytoma. Four types of metanephrine assays were compared: free fractionated plasma metanephrines (232 patients), unfractionated daily urine metanephrines (431 patients), fractionated total daily urine metanephrines (427 patients) and fractionated free daily urine metanephrines (178 patients). The greatest sensitivity was demonstrated by the analysis of free fractionated plasma methanephrines (95.4%). Unlike others, the sensitivity of this analysis did not decrease in the group of patients with small pheochromocytomas (3 cm or less). The greatest specificity was demonstrated by the analysis of unfractionated metanephrines in daily urine (97.8%), with the lowest sensitivity among all tests (67.6%). The study of fractionated total daily urine metanephrins showed good results of sensitivity and specificity, only slightly inferior to the best indicators, and the analysis of free daily urine metanephrins demonstrated unexpectedly low efficiency. There is a positive correlation between the level of metanephrine in the blood and the size of the tumor.
CONCLUSION
Based on the data obtained, the preferred assays for the primary diagnosis of pheochromocytoma can be considered the determination of fractionated free plasma metanephrines and fractionated total daily urine metanephrines, which is consistent with relevant clinical recommendations. It was found that the size of the tumor correlates with the severity of an increase in the level of metanephrins determined by any of the described methods.
Topics: Pheochromocytoma; Humans; Metanephrine; Adrenal Gland Neoplasms; Female; Retrospective Studies; Male; Middle Aged; Adult; Aged
PubMed: 38796760
DOI: 10.14341/probl13309 -
The Journal of Pathology May 2024Neuroendocrine neoplasms (NENs) encompass tumors arising from neuroendocrine cells in various organs, including the gastrointestinal tract, pancreas, adrenal gland, and...
Neuroendocrine neoplasms (NENs) encompass tumors arising from neuroendocrine cells in various organs, including the gastrointestinal tract, pancreas, adrenal gland, and paraganglia. Despite advancements, accurately predicting the aggressiveness of gastroenteropancreatic (GEP) NENs based solely on pathological data remains challenging, thereby limiting optimal clinical management. Our previous research unveiled a crucial link between hypermethylation of the protocadherin PCDHGC3 gene and neuroendocrine tumors originating from the paraganglia and adrenal medulla. This epigenetic alteration was associated with increased metastatic potential and succinate dehydrogenase complex (SDH) dysfunction. Expanding upon this discovery, the current study explored PCDHGC3 gene methylation within the context of GEP-NENs in a cohort comprising 34 cases. We uncovered promoter hypermethylation of PCDHGC3 in 29% of GEP-NENs, with a significantly higher prevalence in gastrointestinal (GI) neuroendocrine carcinomas (NECs) compared with both pancreatic (Pan) NECs and neuroendocrine tumors (NETs) of GI and Pan origin. Importantly, these findings were validated in one of the largest multi-center GEP-NEN cohorts. Mechanistic analysis revealed that PCDHGC3 hypermethylation was not associated with SDH mutations or protein loss, indicating an SDH-independent epigenetic mechanism. Clinically, PCDHGC3 hypermethylation emerged as a significant prognostic factor, correlating with reduced overall survival rates in both patient cohorts. Significantly, whereas PCDHGC3 hypermethylation exhibited a strong correlation with TP53 somatic mutations, a hallmark of NEC, its predictive value surpassed that of TP53 mutations, with an area under the curve (AUC) of 0.95 (95% CI 0.83-1.0) for discriminating GI-NECs from GI-NETs, highlighting its superior predictive performance. In conclusion, our findings position PCDHGC3 methylation status as a promising molecular biomarker for effectively stratifying patients with GI-NENs. This discovery has the potential to advance patient care by enabling more precise risk assessments and tailored treatment strategies. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
PubMed: 38795318
DOI: 10.1002/path.6291 -
International Journal of Molecular... May 2024Gap junctions (GJs) are important in the regulation of cell growth, morphology, differentiation and migration. However, recently, more attention has been paid to their... (Review)
Review
Gap junctions (GJs) are important in the regulation of cell growth, morphology, differentiation and migration. However, recently, more attention has been paid to their role in the pathogenesis of different diseases as well as tumorigenesis, invasion and metastases. The expression pattern and possible role of connexins (Cxs), as major GJ proteins, under both physiological and pathological conditions in the adrenal gland, were evaluated in this review. The databases Web of Science, PubMed and Scopus were searched. Studies were evaluated if they provided data regarding the connexin expression pattern in the adrenal gland, despite current knowledge of this topic not being widely investigated. Connexin expression in the adrenal gland differs according to different parts of the gland and depends on ACTH release. Cx43 is the most studied connexin expressed in the adrenal gland cortex. In addition, Cx26, Cx32 and Cx50 were also investigated in the human adrenal gland. Cx50 as the most widespread connexin, along with Cx26, Cx29, Cx32, Cx36 and Cx43, has been expressed in the adrenal medulla with distinct cellular distribution. Considerable effort has recently been directed toward connexins as therapeutically targeted molecules. At present, there exist several viable strategies in the development of potential connexin-based therapeutics. The differential and hormone-dependent distribution of gap junctions within adrenal glands, the relatively large gap junction within this gland and the increase in the gap junction size and number following hormonal treatment would indicate that gap junctions play a pivotal role in cell functioning in the adrenal gland.
Topics: Humans; Connexins; Gap Junctions; Adrenal Gland Neoplasms; Carcinogenesis; Adrenal Glands; Animals; Gene Expression Regulation, Neoplastic
PubMed: 38791437
DOI: 10.3390/ijms25105399 -
International Journal of Molecular... May 2024Sympathetic nervous system (SNS) hyperactivity is mediated by elevated catecholamine (CA) secretion from the adrenal medulla, as well as enhanced norepinephrine (NE)...
Sympathetic nervous system (SNS) hyperactivity is mediated by elevated catecholamine (CA) secretion from the adrenal medulla, as well as enhanced norepinephrine (NE) release from peripheral sympathetic nerve terminals. Adrenal CA production from chromaffin cells is tightly regulated by sympatho-inhibitory α-adrenergic (auto)receptors (ARs), which inhibit both epinephrine (Epi) and NE secretion via coupling to Gi/o proteins. α-AR function is, in turn, regulated by G protein-coupled receptor (GPCR)-kinases (GRKs), especially GRK2, which phosphorylate and desensitize them, i.e., uncouple them from G proteins. On the other hand, the short-chain free fatty acid (SCFA) receptor (FFAR)-3, also known as GPR41, promotes NE release from sympathetic neurons via the Gi/o-derived free Gβγ-activated phospholipase C (PLC)-β/Ca signaling pathway. However, whether it exerts a similar effect in adrenal chromaffin cells is not known at present. In the present study, we examined the interplay of the sympatho-inhibitory α-AR and the sympatho-stimulatory FFAR3 in the regulation of CA secretion from rat adrenal chromaffin (pheochromocytoma) PC12 cells. We show that FFAR3 promotes CA secretion, similarly to what GRK2-dependent α-AR desensitization does. In addition, FFAR3 activation enhances the effect of the physiologic stimulus (acetylcholine) on CA secretion. Importantly, GRK2 blockade to restore α-AR function or the ketone body beta-hydroxybutyrate (BHB or 3-hydroxybutyrate), via FFAR3 antagonism, partially suppress CA production, when applied individually. When combined, however, CA secretion from PC12 cells is profoundly suppressed. Finally, propionate-activated FFAR3 induces leptin and adiponectin secretion from PC12 cells, two important adipokines known to be involved in tissue inflammation, and this effect of FFAR3 is fully blocked by the ketone BHB. In conclusion, SCFAs can promote CA and adipokine secretion from adrenal chromaffin cells via FFAR3 activation, but the metabolite/ketone body BHB can effectively inhibit this action.
Topics: Animals; PC12 Cells; Rats; Receptors, G-Protein-Coupled; Catecholamines; Receptors, Adrenergic, alpha-2; Adipokines; Chromaffin Cells; Signal Transduction; Norepinephrine
PubMed: 38791266
DOI: 10.3390/ijms25105227