Pheochromocytoma is a tumor derived from chromaffin tissue in the adrenergic system with excessive secretion of catecholamine.Pheochromocytoma occurs at any age of patients,commonly in 40-60 years,and the incidence is slightly higher in women than in men.In recent years,studies have shown that the mutations of von Hippel-Lindau gene (VHL),rearranged during transfection gene (RET),neurofibromatosis type 1 gene (NF-1),succinate dehydrogenase gene (SDH),transmembrane protein 127 gene (TMEM127),myelocytomatosis oncogene-associated factor X gene (MAX) are associated with pheochromocytoma.Immunohistochemical studies have revealed that a number of molecular markers,such as telomerase,vascular endothelial growth factor,cyclooxygenase-2,adrenomedullin,plasma chromaffin protein A,signal transducer and activator of transcription-3 are of value in identification of tumor origin,its biological behaviors and differentiation of pheochromocytoma. This article reviews the newest research progresses in molecular biology of pheochromocytoma.
Adrenal Gland Neoplasms ; genetics ; Biomarkers, Tumor ; genetics ; Humans ; Mutation ; Pheochromocytoma ; genetics

Flow cytometric DNA analysis was performed on 19 adrenal pheochromocytomas and 6 extra-adrenal paragangliomas in parallel with clinical and histopathological review to determine the usefulness of this technique to predict biologic behavior of these tumors. In pheochromocytomas and paragangliomas, tetraploidy or near-tetraploidy occurred in 32% and 33% and aneuploidy in 10% and none respectively. A case of malignant pheochromocytoma had diploid DNA content. Occurrence of aneuploidy or tetraploidy is frequent in clinically benign tumors in conjunction with a marked degree of nuclear atypia and cannot be a predictor of malignancy.
Adolescent ; Adrenal Gland Neoplasms/*genetics/pathology ; Adult ; Age Factors ; Child ; DNA, Neoplasm/*analysis ; Female ; *Flow Cytometry ; Human ; Male ; Middle Age ; Mitosis ; Paraganglioma/*genetics/pathology ; Pheochromocytoma/*genetics/pathology ; Ploidies

OBJECTIVETo investigate the expression of urotensin II (U II) and G-protein coupled receptor 14 (GPR14) mRNA in human pheochromocytoma tissues.

METHODSTotal RNA from normal adrenal and pheochromocytoma tissues was extracted. The reverse transcription-polymerase chain reaction method was used to evaluate the levels of U II and GPR14 mRNA expression in human pheochromocytoma tissues.

RESULTSThere was no significant difference of U II and GPR14 mRNA expression between normal adrenal cortex and medulla. The expression of U II and GPR14 mRNA in pheochromocytoma was significantly lower than that in normal adrenal cortex and medulla (P < 0.05). The expression of GPR14 mRNA in adrenal pheochromocytomas was significantly lower than that of extra-adrenal pheochromocytomas (P < 0.05).

CONCLUSIONU II and GPR14 may play a role in the pathogenesis and hypertension regulating of pheochromocytoma.

Adrenal Cortex ; metabolism ; Adrenal Gland Neoplasms ; metabolism ; Adrenal Medulla ; metabolism ; Humans ; Pheochromocytoma ; metabolism ; RNA, Messenger ; biosynthesis ; genetics ; Receptors, G-Protein-Coupled ; biosynthesis ; genetics ; Urotensins ; biosynthesis ; genetics

OBJECTIVETo investigate the expression of chromogranin A (CgA) and synaptophysin (Syn) for differential diagnosis of different kinds of adrenal gland tumors.

METHODSThe samples of 69 adrenal gland tumors and 4 normal adrenal glands were immunohistochemically analyzed for the expression of chromogranin A and synaptophysin. The statistical analysis of the data was performed using chi-square test.

RESULTSIn the normal adrenal gland, CgA and Syn was exclusively detected in the medulla. CgA was detected in all pheochromocytomas 25/25 (100%), and gave less or no expression in adrenocortical tumors. Syn was detected in adrenocortical adenomas 27/28 (96.4%), adrenocortical carcinoma 7/8 (87.5%), pheochromocytoma 24/25 (96.0%) and adrenal metastatic carcinoma 6/8 (75.0%), respectively.

CONCLUSIONThere is statistically significant difference of CgA expression between adrenalcortical and adrenal medullary tumors, and also between benign and malignant pheochromocytomas. CgA and Syn are immunohistochemically reliable markers in the differential diagnosis of various kinds of adrenal gland tumors.

Adrenal Gland Neoplasms ; diagnosis ; metabolism ; Adrenocortical Adenoma ; diagnosis ; metabolism ; Adrenocortical Carcinoma ; diagnosis ; metabolism ; Chromogranin A ; biosynthesis ; genetics ; Diagnosis, Differential ; Female ; Humans ; Male ; Pheochromocytoma ; diagnosis ; metabolism ; Synaptophysin ; biosynthesis ; genetics

OBJECTIVE: To analyze the germline variations of genes RET, VHL, SDHD and SDHB in patients with pheochromocytoma and/or paraganglioma and to evaluate variations of these genes in Chinese patients. METHODS: Patients who were treated in Peking University First Hospital from September 2012 to March 2014 and diagnosed with pheochromocytoma and/or paraganglioma by pathologists were included in this study. Twelve patients were included in total, of whom 11 had pheochromocytoma, and 1 had paraganglioma. Deoxyribonucleic acid (DNA) was extracted from the leukocytes of peripheral blood of the patients. The exons 10, 11, 13-16 of the RET gene, and all exons of VHL, SDHB and SDHD genes and their nearby introns (±20 bp) were amplified with polymerase chain reactions, and the products were sent to a biotechnology company for sequencing. The sequencing results were compared with wildtype sequences of these genes to identify variations. One of the patients was diagnosed with multiple endocrine neoplasia type 2A. A family analysis was performed in his kindred, and his family members received genetic tests for the related variations. RESULTS: Three patients were found to have germline gene variations. A c.136C>T (p.R46X) variation of the SDHB gene was found in a patient with malignant pheochromocytoma. A c.1901G>A (C634Y) variation, as well as c.2071G>A (p.G691S) and c.2712C>G (p.S904S) variations of the RET gene were found in a patient with multiple endocrine neoplasia type 2A. After a family analysis, five family members of this patient were found to have the same variations. c.2071G>A (p.G691S) and c.2712C>G (p.S904S) variations of the RET gene were also found in a clinical sporadic patient without evidence of malignancy. A patient with congenital single ventricle malformation and pheochromocytoma was included in this study, and no variation with clinical significance was found in the four genes of this patient. CONCLUSION 25% (3/12) patients with pheochromocytoma or paraganglioma were found to have missense or nonsense germline gene variations in this study, including the c.136C>T (p.R46X) variation of the SDHB gene, the c.1901G>A (C634Y) variation of the RET gene, and c.2071G>A (p.G691S) and c.2712C>G (p.S904S) variations of the RET gene. The former two variations have already been confirmed to be pathogenic. The existence of these variations in Chinese patients with pheochromocytoma and/or paraganglioma was validated in this study, which supports the conclusion that genetic testing is necessary to be generally performed in patients with pheochromocytoma and/or paraganglioma.
Adrenal Gland Neoplasms/genetics* ; Genetic Testing ; Germ-Line Mutation ; Humans ; Paraganglioma/genetics* ; Pheochromocytoma/genetics* ; Proto-Oncogene Proteins c-ret/genetics* ; Succinate Dehydrogenase/genetics* ; Von Hippel-Lindau Tumor Suppressor Protein/genetics*

OBJECTIVETo compare the expressions of transforming growth factor alpha (TGFalpha), tumor necrosis factor alpha (TNFalpha), and vascular endothelial growth factor (VEGF) between pheochromocytoma (PHEO) tissues and normal adrenal medulla tissues.

METHODSThe mRNA expressions of TGFalpha, TNFalpha, and VEGF detected by RT-PCR, were compared between 22 PHEO tissues and 18 normal adrenal medulla tissues (according with the principle of medical ethnics). Immunohistochemistry staining was performed on 27 PHEO tissues and 14 normal adrenal medulla tissues. The comparisons of the protein expression of TGFalpha, TNFalpha, and VEGF were analyzed in both of PHEO tissues and normal adrenal medulla tissues.

RESULTSCompared with normal adrenal medulla tissues, the expressions of TGFalpha and TNFalpha mRNA and protein were higher in PHEO tissues, and VEGF145 mRNA expression was also higher in PHEO tissues, while there was no significant difference of the mRNA expression of VEGF121 and VEGF165 between these two tissues. Positive staining rates for VEGF of endothelial cells and tumor cells were higher in PHEO tissues than in normal adrenal medulla tissues. Expressions of the TGFalpha, TNFalpha, and VEGF protein were higher in extra-adrenal PHEO than in adrenal PHEO. The TNFalpha immunohistochemistry staining rate was higher in the malignant or multiple PHEO than in the benign or single PHEO.

CONCLUSIONSThe mRNA and protein expressions of TGFalpha, TNFalpha, and VEGF are higher in PHEO tissues than those in normal adrenal medulla tissues. Expressions of these cytokines vary in PHEO with different characteristic.

Adrenal Gland Neoplasms ; metabolism ; Adrenal Medulla ; metabolism ; Humans ; Pheochromocytoma ; metabolism ; RNA, Messenger ; biosynthesis ; genetics ; Transforming Growth Factor alpha ; biosynthesis ; genetics ; Tumor Necrosis Factor-alpha ; biosynthesis ; genetics ; Vascular Endothelial Growth Factors ; biosynthesis ; genetics

OBJECTIVETo carry out a genetic detection and analysis of Von Hippel-Lindau (VHL) gene in Chinese patients with sporadic pheochromocytoma.

METHODSDNA samples were extracted from peripheral blood cells and fresh pheochromocytoma specimens from 41 patients with sporadic pheochromocytoma were assayed by polymerase chain reaction and direct sequencing. The DNA samples of 50 healthy volunteers were extracted from peripheral blood as a control. The PCR products of exon 1, exon 2 and exon 3 were used for molecular analysis of the VHL gene. The genetic detection of family members of VHL gene mutations was also performed.

RESULTSOne of mutations was located at nucleotide 572 (G-->C) in exon 2, presenting a codon 120 from arginine (R) to threonine (T). Tow small insertions were locatated at nucleotide 623T (TTTGTtG) in exon 2, leading to a frameshift mutation. There were also three carriers of G572C and three carriers of 623T (TTTGTtG) in family members of the three cases.

CONCLUSIONThere are some Chinese patients with sporadic pheochromocytoma with tumorigenic VHL gene mutations. It is recommended to use the genetic detection and analysis of VHL gene as a routine examination for patients with sporadic pheoehromoeytoma under the age of 50 years with questionable family history. The genetic detection and analysis of VHL gene may be useful as a marker for the diagnosis of hereditary pheochromocytoma.

Adrenal Gland Neoplasms ; genetics ; Adult ; DNA Mutational Analysis ; DNA, Neoplasm ; genetics ; Exons ; Family ; Female ; Humans ; Male ; Middle Aged ; Mutation ; Pedigree ; Pheochromocytoma ; genetics ; Von Hippel-Lindau Tumor Suppressor Protein ; genetics

OBJECTIVETo investigate the clinical and genetic features of a Chinese family with von Hippel-Lindau (VHL) disease revealed by bilateral pheochromocytoma.

METHODSThe proband and other members in a Chinese family with familial pheochromocytoma were clinically evaluated and followed up. Genomic DNA extracted from the peripheral blood of 8 family members (including 3 patients) was amplified by polymerase chain reaction (PCR) and the PCR products were directly sequenced.

RESULTSThe first presentation in the proband, his mother, and his sister was bilateral pheochromocytoma, and the missense mutation of 695G-A (Arg161Gln) in exon 3 of VHL gene was detected in the three patients. In the follow-up study, the proband and his mother were found to have other VHL tumors, induding retinal and cerebellar hemangioblastomas and pancreatic tumor. Neither clinical presentation of VHL disease nor gene mutation was found in other family members.

CONCLUSIONVHL disease should be suspected in some patients with familial pheochromocytoma, and VHL gene screening helps to achieve early diagnosis of the disease.

Adrenal Gland Neoplasms ; diagnostic imaging ; genetics ; Adult ; Female ; Humans ; Male ; Middle Aged ; Mutation ; Pheochromocytoma ; diagnostic imaging ; genetics ; Tomography, X-Ray Computed ; Von Hippel-Lindau Tumor Suppressor Protein ; genetics ; von Hippel-Lindau Disease ; diagnostic imaging ; genetics

OBJECTIVETo investigate the potential diagnostic value of A103 and inhibin-alpha in adrenocortical tumors and to evaluate the applicability of tissue microarray/tissue chip in pathological studies using immunohistochemistry.

METHODSA tissue microarray/tissue chip was constructed to contain 179 formalin-fixed, paraffin-embedded adrenal tissue samples which include 3 normal adrenal cortex, 2 fetal adrenal cortex, 2 nodular adrenocortical hyperplasia samples, 72 adrenocortical adenomas, 39 adrenocortical carcinomas, 3 adrenal medulla, 13 metastatic carcinomas, 4 metastatic malignant melanomas and 44 pheochromocytomas. Additional 20 cases of normal adult adrenal gland were used as controls. Immunohistochemical markers, including A103, inhibin-alpha, calretinin and Ki-67 were used on the tissue array sections by EnVision immunohistochemical staining methods.

RESULTSPositive staining of A103 was seen in all of the 23 (100%) adrenal cortex, 2 fetal adrenal cortex, 2 nodular adrenocortical hyperplasia samples, 60 of 66 (90.9%) adrenocortical adenomas samples, 35 of 37 (94.6%) adrenocortical carcinomas samples, 3 of 3 malignant melanomas, but in none of the adrenal medulla, pheochromocytomas or adrenal metastatic carcinoma samples. In all of the adrenal cortex, fetal adrenal cortex and nodular adrenocortical hyperplasia cases, inhibin-alpha immunoreactivity was limited to the zona reticularis and the innermost zona fasciculata. Fifty of the 66 (75.8%) adrenocortical adenomas, 28 of the 37 (75.7%) adrenocortical carcinomas were positive for inhibin-alpha. None of the adrenal medulla, pheochromocytoma, metastatic malignant melanoma or carcinoma samples showed a positive inhibin-alpha immunostain.

CONCLUSIONSThe tissue microarray/tissue chip technique provides a reliable method to investigate marker expression by offering a rapid, economic and accurate screening of tissue specimens on a large scale. The combined use of A103 and inhibin-alpha is valuable in distinguishing adrenocortical tumor from pheochromocytoma and other metastatic neoplasms.

Adrenal Cortex ; metabolism ; Adrenal Cortex Neoplasms ; diagnosis ; metabolism ; secondary ; Adrenocortical Adenoma ; diagnosis ; metabolism ; Adult ; Antigens, Neoplasm ; biosynthesis ; genetics ; Female ; Humans ; Immunohistochemistry ; Inhibins ; biosynthesis ; genetics ; MART-1 Antigen ; Male ; Neoplasm Proteins ; biosynthesis ; genetics ; Oligonucleotide Array Sequence Analysis ; Pheochromocytoma ; diagnosis ; metabolism

OBJECTIVE: To explore the pathological characteristics and significance of RET proto-oncogene screening in multiple endocrine neoplasia type 2A (MEN2A) with cutaneous lichen amyloidosis (CLA). METHODS: Clinical data of 51 members from 7 unrelated pedigrees of MEN2A-CLA were collected. Systemic clinical investigations including biochemical testing, imaging examination, germline RET variant screening and histopathological examination were carried out. RESULTS: RET gene variants were detected in 28 patients with MEN2A (C634G/F/R/S/W and C611Y) including 12 males and 16 females, with the mean age of diagnosis being (41.1 ± 18.3) years old, which were consistent with their clinical manifestations. The incidence of medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), hyperparathyroidism (HPTH) and CLA among 28 MEN2A patients were 89.3%, 28.6%, 7.1% and 28.6%, respectively. Comparison of the incidence of MTC/PHEO/HPTH and CLA between C611Y and C634G/F/R/S/W, only PHEO and CLA in C611Y were lower than those in C634G/F/R/S/W (P < 0.05; P < 0.05). Among 8 patients with CLA, the male to female ratio was 2 : 6. The clinical features included pruritus in the interscapular region and presence of dry, thickened, scaly, brown pigment, clustered or desquamate-like plaques. The mean onset age of CLA [(18.4 ± 4.6) years] versus the mean age at diagnosis of CLA or MEN2A were significantly different (P < 0.001; P < 0.001). CONCLUSION MEN2A-CLA may be the early clinical manifestation of MEN2A and most frequently occurred along with RET-C634 variant. To facilitate the recognition of MEN2A-CLA, to combine family investigation and screening of RET variant are helpful for early diagnosis and standardized treatment, which can improve the long-term outcome of MEN2A-specific tumors.
Adolescent ; Adrenal Gland Neoplasms ; Adult ; Amyloidosis, Familial ; Carcinoma, Neuroendocrine ; China ; Female ; Humans ; Lichens ; Male ; Middle Aged ; Multiple Endocrine Neoplasia Type 2a/genetics* ; Pheochromocytoma ; Proto-Oncogene Proteins c-ret/genetics* ; Skin Diseases, Genetic ; Thyroid Neoplasms/genetics* ; Young Adult