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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 -
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 -
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 -
Radiology Case Reports Aug 2024Adrenal schwannoma is a rare tumor of Schwann cell origin that represents less than 0.2% of all adrenal tumors. These typically benign tumors are most often found in the...
Adrenal schwannoma is a rare tumor of Schwann cell origin that represents less than 0.2% of all adrenal tumors. These typically benign tumors are most often found in the head, neck, and limbs. However, schwannomas can also rarely occur rarely in the adrenal gland within the retroperitoneal cavity. In the adrenal gland, these tumors arise from the medulla and are difficult to diagnose, often misdiagnosed as other benign or malignant entities. In this article, we report the case of a 43-year-old female with a large left adrenal mass revealed by biopsy to be a schwannoma. We focus on the use of radiological imaging modalities and immunohistochemical analysis to optimize diagnosis and treatment intervention of this rare tumor.
PubMed: 38741689
DOI: 10.1016/j.radcr.2024.04.036 -
Journal of Zhejiang University.... Mar 2024Pheochromocytomas and paragangliomas (PPGLs) cause symptoms by altering the circulation levels of catecholamines and peptide hormones. Currently, the diagnosis of PPGLs...
Pheochromocytomas and paragangliomas (PPGLs) cause symptoms by altering the circulation levels of catecholamines and peptide hormones. Currently, the diagnosis of PPGLs relies on diagnostic imaging and the detection of catecholamines. In this study, we used ultra-performance liquid chromatography (UPLC)/quadrupole time-of-flight mass spectrometry (Q-TOF MS) analysis to identify and measure the perioperative differential metabolites in the plasma of adrenal pheochromocytoma patients. We identified differentially expressed genes by comparing the transcriptomic data of pheochromocytoma with the normal adrenal medulla. Through conducting two steps of metabolomics analysis, we identified 111 differential metabolites between the healthy group and the patient group, among which 53 metabolites were validated. By integrating the information of differential metabolites and differentially expressed genes, we inferred that the cysteine-methionine, pyrimidine, and tyrosine metabolism pathways were the three main metabolic pathways altered by the neoplasm. The analysis of transcription levels revealed that the tyrosine and cysteine-methionine metabolism pathways were downregulated in pheochromocytoma, whereas the pyrimidine pathway showed no significant difference. Finally, we developed an optimized diagnostic model of two metabolites, L-dihydroorotic acid and vanylglycol. Our results for these metabolites suggest that they may serve as potential clinical biomarkers and can be used to supplement and improve the diagnosis of pheochromocytoma.
Topics: Pheochromocytoma; Humans; Adrenal Gland Neoplasms; Pyrimidines; Methionine; Tyrosine; Cysteine; Male; Metabolomics; Female; Middle Aged; Adult; Metabolic Networks and Pathways
PubMed: 38725340
DOI: 10.1631/jzus.B2300579 -
Case Reports in Oncological Medicine 2024Paragangliomas are rare neuroendocrine tumors that arise from the paraganglia, which are clusters of neuroendocrine cells associated with the autonomic nervous system....
Paragangliomas are rare neuroendocrine tumors that arise from the paraganglia, which are clusters of neuroendocrine cells associated with the autonomic nervous system. These tumors are commonly found in the adrenal medulla but can also occur in other locations outside the adrenal gland. Here, we present a case report of a slow-growing paraganglioma in the left neck with spinal metastasis in a 60-year-old man. This case highlights the importance of considering paraganglion tumors in the differential diagnosis of neck masses and the need for early diagnosis and management to prevent potential complications. Importantly, both the clinical picture and anatomical location of these tumors is important when determining treatment plans.
PubMed: 38706789
DOI: 10.1155/2024/2025115