嗜铬细胞瘤分子病因学研究进展

嗜铬细胞瘤/副神经节瘤(pheochromocytoma/paraganglioma,PPGL)是一种罕见的神经内分泌肿瘤,约40%的PPGL具有家族遗传性,其发病与已知致病基因的胚系突变相关。此外,肿瘤的体细胞基因突变、拷贝数变异、甲基化程度和非编码RNA也参与PPGL的发生。全面和深入了解PPGL的发病机制,将为今后寻找新的治疗靶点提供思路。文章总结了近几年在PPGL的发病机制方面取得的新进展。     

SDH基因与嗜铬细胞瘤

编码线粒体琥珀酸脱氢酶B、D亚单位 (SDHB、SDHD)的基因突变可造成氧感受通路异常 ,参与肿瘤的血管形成 ,它们作为抑癌基因在头颈部家族性副神经节瘤的发病中起重要作用。其在家族性和散发性嗜铬细胞瘤中是否存在突变 ,目前结果还不一致。但SDHD和SDHB基因突变应作为嗜铬细胞瘤的基因检测的项目之一。     

SDH基因与嗜铬细胞瘤

编码线粒体琥珀酸脱氢酶B、D亚单位(SDHB、SDHD)的基因突变可造成氧感受通路异常，参与肿瘤的血管形成，它们作为抑癌基因在头颈部家族性副神经节瘤的发病中起重要作用。其在家族性和散发性嗜铬细胞瘤中是否存在突变，目前结果还不一致。但SDHD和SDHB基因突变应作为嗜铬细胞瘤的基因检测的项目之一。     

嗜铬细胞瘤/副神经节瘤的诊疗进展

嗜铬细胞瘤/副神经节瘤(PPGL)是一组起源于肾上腺髓质或肾上腺外交感神经链的神经内分泌肿瘤，是难治性高血压的病因之一。近年来，基于基因检测技术的快速发展和功能成像等影像学技术的广泛应用，PPGL的检出率和诊断率显著提高，并为PPGL的治疗提供了新的方法。目前，一些新疗法已经开展或正在进行临床试验，本文将对PPGL的诊治新进展进行综述。     

散发性嗜铬细胞瘤患者SDHB基因突变筛查

应用PCR扩增102例嗜铬细胞瘤患者抑癌基因SDHB并直接测序,结果显示有3例患者存在基因突变.分别为2号外显子CGA→TGA(R46X)、3号外显子CGA→TGA(Rgox)和7号外显子CGC→CAC(R242H),推测抑癌基因SDHB在散发性嗜铬细胞瘤患者中的突变率约为3%.     

原发性气管副神经节瘤1例并文献复习

正副神经节瘤(Paraganglioma)是起源于副交感神经节的肿瘤,大多数是良性肿瘤,按其主细胞对铬盐的反应,有嗜铬性和非嗜铬性之分,嗜铬细胞瘤是肾上腺髓质副神经节瘤的典型代表。副神经节瘤可发生于身体各个部位,以副神经节丰富区域居多,而发生于气管内的副神经节瘤罕见,目前国内外仅有近20例患者报道,现报道我院收治的1例气管副神经节瘤患者临床、影像学、病理学特征,回顾性分析相关文献并总结,以提高临床医生对气管副神经节瘤的诊疗。临床资料     

小嗜铬细胞瘤副神经节瘤21例临床特征分析

目的分析小的嗜铬细胞瘤副神经节瘤(pheochromocytoma and paraganglioma,PPGL)的临床特征,提高医务人员对小PPGL的认识。方法回顾性分析2011年4月至2016年2月就诊于重庆医科大学附属第一医院的103例PPGL患者的临床资料,根据术前CT提示最大直径分为小PPGL组(直径≤3 cm)和较大PPGL组(直径3 cm),比较两组间临床表现、血浆游离甲氧基肾上腺素类物质(MNs)、影像学和病理学特征、围术期情况等的差异。结果小PPGL组21例,肿瘤平均直径为(2.39±0.67) cm。小PPGL组患者头痛、心悸、多汗、其他PPGL临床表现和至少具有嗜铬细胞瘤经典三联征的两种表现的发生率均低于较大肿瘤组,且小PPGL组内三联征症状均不具备者所占比例高于较大肿瘤组,但差异均缺乏统计学意义。小PPGL组血浆甲氧基肾上腺素和甲氧基去甲肾上腺素均显著低于较大PPGL组,小PPGL组血浆游离MNs水平轻微升高和正常的发生率均显著高于较大肿瘤组。两组PPGL在CT上有一些相似表现,平扫时CT值均大于10 Hu,绝大部分PPGL平扫CT值大于20 Hu,在增强CT上均主要表现为明显强化。小PPGL组患者术前误诊率明显高于较大肿瘤组。小PPGL组患者手术时间及术中出血量明显少于较大肿瘤组。结论小PPGL并不少见,临床表现往往不典型,生化标志物更多的表现为轻微升高或正常,而解剖和功能成像有助于识别本病,尤其多种临床资料综合分析可减少小PPGL的漏诊、误治。     

肾上腺外副神经节瘤诊断治疗现状

1908年Alezai’s和Peyron首先报道了一组副神经节瘤病，1912年，Pick建议将肾上腺内嗜铬细胞瘤命名嗜铬细胞瘤，而肾上腺外嗜铬性肿瘤称副神经节瘤。传统认为副神经节瘤仅占全部嗜铬细胞瘤的10％-15％，近年来国内报道有上升的趋势，多数报道在20％左右。     

恶性嗜铬组织肿瘤的诊断进展

嗜铬组织肿瘤主要包括嗜铬细胞瘤及副神经节瘤,其中10%的嗜铬细胞瘤为恶性,而副神经节瘤的恶性发生率更高.目前临床表现、生化指标及组织病理学结果并不能完全区分肿瘤的良恶性.一些影像学方法对于肿瘤的定性、定位诊断有特殊的意义.近年来根据基因表达谱来鉴别嗜铬组织肿瘤的良、恶性已成为日后研究的方向.     

嗜铬细胞瘤和副神经节瘤的诊断与临床管理

嗜铬细胞瘤和副神经节瘤(pheochromocytoma and paraganglioma,PPGL)临床少见但不罕见。因其临床表现多样且严重程度不一,常容易漏诊误诊;同时,PPGL的治疗过程常因缺乏循证医学依据指导,临床医生的决策严重依赖经验,故而经验缺乏的临床机构常常在诊疗上困难重重,并且难以实现正确而充分的术前准备。为了规范PPGL的诊疗过程以及帮助基层医疗机构更好地识别、诊断、治疗PPGL,本中心参考近年来国内外最新相关指南、荟萃分析并结合国内研究完成该文。     

R46Q mutation in the succinate dehydrogenase B gene (SDHB) in a Japanese family with both abdominal and thoracic paraganglioma following metastasis

Recently, nuclear genes encoding two mitochondrial complex II subunit proteins, SDHD and SDHB, have been found to be associated with the development of familial pheochromocytomas and paragangliomas (hereditary pheochromocytoma/paraganglioma syndrome: HPPS). Growing evidence suggests that a mutation of SDHB is highly associated with abdominal (or thoracic) paraganglioma and the following distant metastasis (malignant paraganglioma). Previously, we identified a novel heterozygous G to A point mutation at the first base of intron 3 of the SDHB gene (IVS3+1G>A) in a malignant abdominal paraganglioma from a Japanese patient. In the present study, we report another case of SDHB mutation (R46Q) in a Japanese patient with both abdominal and thoracic paraganglioma following malignant metastasis. In addition, we identified an asymptomatic carrier of SDHB mutation in this family. Our report highlights the pathogenic role of the SDHB mutation (R46Q) in malignant paraganglioma. We also discuss the desired protocol that should be adopted to follow up an asymptomatic carrier of this mutation.     

The malignant potential of a succinate dehydrogenase subunit B germline mutation

Familial catecholamine secreting tumors have been associated with multiple endocrine neoplasia type 2, Von Hippel-Lindau disease and neurofibromatosis type 1. In the last years, mutations of genes encoding subunits B, C and D of the succinate dehydrogenase have been discovered as other causes of pheochromocytomas and paragangliomas. We diagnosed a malignant retroperitoneal paraganglioma in a 64-yr-old man with bone metastasis in 2001. Two years later a retroperitoneal benign paraganglioma was found and resected in his 32-yr-old daughter. Thus we diagnosed in this family a paraganglioma syndrome. We performed molecular genetic analyses of the genes SDHB, SDHC, and SDHD. We detected in the SDHB gene the mutation SDHB c. 558-3 C> G affecting the splice site of exon 5. In a second daughter the mutation was also detected, thorough clinical investigation revealed normal results. We conclude that the SDHB mutation predisposes to abdominal extra-adrenal and potential malignant pheochromocytoma with incomplete penetrance.     

High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing

CONTEXT: Adrenal and extraadrenal paragangliomas are tumors of chromaffin cells that are usually benign but that may also develop into malignant disease. Mutations of the gene for succinate dehydrogenase subunit B (SDHB) are associated with a high risk of malignancy, but establishing the precise contribution requires relatively large numbers of patients with well-defined malignancy. OBJECTIVE: We assessed the prevalence of SDHB mutations in a series of patients with malignant paraganglioma. DESIGN: SDHB mutation testing was carried out in 44 consecutive patients with malignant paraganglioma. Clinical characteristics of patients with malignant disease due to SDHB mutations were compared with those without mutations. RESULTS: Pathogenic SDHB mutations were found in 13 of the 44 patients (30%). Close to one third of patients had metastases originating from an adrenal primary tumor, compared with a little over two thirds from an extraadrenal tumor. Among the latter patients, the frequency of SDHB mutations was 48%. CONCLUSION: This study establishes that missense, nonsense, frameshift, and splice site mutations of the SDHB gene are associated with about half of all malignancies originating from extraadrenal paragangliomas. The high frequency of SDHB germline mutations among patients with malignant disease, particularly when originating from an extraadrenal paraganglioma, may justify a high priority for SDHB germline mutation testing in these patients.     

A thyroid nodule revealing a paraganglioma in a patient with a new germline mutation in the succinate dehydrogenase B gene

A 32-year-old asymptomatic female was diagnosed with an isolated thyroid nodule of 2.5 cm diameter. Fine needle aspiration suggested a medullary thyroid carcinoma. Consequently, a total thyroidectomy was performed. The nodule stained positive for chromogranin A, neurone-specific enolase and synaptophysin, but not for calcitonin. Finally, pathological analysis showed a thyroid paraganglioma. Although the tumour appeared to be sporadic in a patient with no personal or familial history of paraganglioma and/or pheochromocytoma, we have identified a new mutation (392delC) of the succinate dehydrogenase-B (SDHB) gene in the genomic DNA extracted from the leukocytes of the patient. That mutation induced a shift in the reading frame of the gene creating a premature stop codon (P131fsX135) which was predicted to result in a truncated SDHB protein of 135 amino acids.This report highlights the difficulties of this unexpected diagnosis of hereditary thyroid paraganglioma. It also discusses the clinical involvements in terms of familial screening and the necessary follow-up of the patient.     

Role of positron emission tomography and bone scintigraphy in the evaluation of bone involvement in metastatic pheochromocytoma and paraganglioma: specific implications for succinate dehydrogenase enzyme subunit B gene mutations

We performed a retrospective analysis of 71 subjects with metastatic pheochromocytoma and paraganglioma (30 subjects with mutation of succinate dehydrogenase enzyme subunit B (SDHB) gene and 41 subjects without SDHB mutation). Sixty-nine percent presented with bone metastases (SDHB +/-: 77% vs 63%), 39% with liver metastases (SDHB +/-: 27% vs 47%), and 32% with lung metastases (SDHB +/-: 37% vs 29%). The most common sites of bone involvement were thoracic spine (80%; SDHB+/-: 83% vs 77%), lumbar spine (78%; SDHB +/-: 78% vs 75%), and pelvic and sacral bones (78%; SDHB +/-: 91% vs 65%, P=0.04). Subjects with SDHB mutation also showed significantly higher involvement of long bones (SDHB +/-: 78% vs 30%, P=0.007) than those without the mutation. The best overall sensitivity in detecting bone metastases demonstrated positron emission tomography (PET) with 6-[(18)F]-fluorodopamine ([(18)F]-FDA; 90%), followed by bone scintigraphy (82%), computed tomography or magnetic resonance imaging (CT/MRI; 78%), 2-[(18)F]-fluoro-2-deoxy-d-glucose ([(18)F]-FDG) PET (76%), and scintigraphy with [(123/131)I]-metaiodobenzylguanidine (71%). In subjects with SDHB mutation, imaging modalities with best sensitivities for detecting bone metastases were CT/MRI (96%), bone scintigraphy (95%), and [(18)F]-FDG PET (92%). In subjects without SDHB mutations, the modality with the best sensitivity for bone metastases was [(18)F]-FDA PET (100%). In conclusion, bone scintigraphy should be used in the staging of patients with malignant pheochromocytoma and paraganglioma, particularly in patients with SDHB mutations. As for PET imaging, [(18)F]-FDG PET is highly recommended in SDHB mutation patients, whereas [(18)F]-FDA PET is recommended in patients without the mutation.     

Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene

Approximately 10% of catecholamine-secreting tumors are malignant, and 10% are familial. These tumors have been associated with several hereditary syndromes, including multiple endocrine neoplasia type 2, von Hippel-Lindau syndrome, neurofibromatosis type 1, and familial paraganglioma. Mutations in succinate dehydrogenase (SDH) subunit genes have been identified in some kindreds with catecholamine-secreting tumors. In 1972 at the Mayo Clinic, a metastatic catecholamine-secreting paraganglioma was diagnosed in a 32-yr-old man. In 1979, 7 yr after the initial surgical treatment, a lytic metastasis to the left femur was found and was treated with local external radiotherapy. Locally metastatic abdominal catecholamine-secreting paragangliomas were diagnosed in the patient's 27-yr-old son. Analyses of the VHL, RET, SDHD, and SDHC genes revealed no mutations. However, a missense point mutation was detected in the SDHB gene: c.725G-->A in exon 7, which alters a conserved arginine at amino acid position 242 to a histidine (R242H). Sequencing of the SDHB gene in the tumors did not reveal any somatic mutations or loss of heterozygosity of the remaining allele. Thirty years after the initial diagnosis, the father is one of the longest living survivors of malignant catecholamine-secreting paraganglioma. Our findings indicate that mutations in SDHB may be associated with metastatic, yet clinically indolent, abdominal paraganglioma in some families.     

Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes

CONTEXT: The identification of mutations in genes encoding peptides of succinate dehydrogenase (SDH) in pheochromocytoma/paraganglioma syndromes has necessitated clear elucidation of genotype-phenotype associations. OBJECTIVE: Our objective was to determine genotype-phenotype associations in a cohort of patients with pheochromocytoma/paraganglioma syndromes and succinate dehydrogenase subunit B (SDHB) or subunit D (SDHD) mutations. DESIGN, SETTING, AND PARTICIPANTS: The International SDH Consortium studied 116 individuals (83 affected and 33 clinically unaffected) from 62 families with pheochromocytoma/paraganglioma syndromes and SDHB or SDHD mutations. Clinical data were collected between August 2003 and September 2004 from tertiary referral centers in Australia, France, New Zealand, Germany, United States, Canada, and Scotland. MAIN OUTCOME MEASURES: Data were collected on patients with pheochromocytomas and/or paragangliomas with respect to onset of disease, diagnosis, genetic testing, surgery, pathology, and disease progression. Clinical features were evaluated for evidence of genotype-phenotype associations, and penetrance was determined. RESULTS: SDHB mutation carriers were more likely than SDHD mutation carriers to develop extraadrenal pheochromocytomas and malignant disease, whereas SDHD mutation carriers had a greater propensity to develop head and neck paragangliomas and multiple tumors. For the index cases, there was no difference between 43 SDHB and 19 SDHD mutation carriers in the time to first diagnosis (34 vs. 28 yr, respectively; P = 0.3). However, when all mutation carriers were included (n = 112), the estimated age-related penetrance was different for SDHB vs. SDHD mutation carriers (P = 0.008). CONCLUSIONS: For clinical follow-up, features of SDHB mutation-associated disease include a later age of onset, extraadrenal (abdominal or thoracic) tumors, and a higher rate of malignancy. In contrast, SDHD mutation carriers, in addition to head and neck paragangliomas, should be observed for multifocal tumors, infrequent malignancy, and the possibility of extraadrenal pheochromocytoma.     

A SDHB malignant paraganglioma with dramatic response to temozolomide-capecitabine

Ten percent of paragangliomas are malignant and one-third occurs in a genetic background. We report a case of succinate dehydrogenase subunit B (SDHB)-related malignant paraganglioma with dramatic response to temozolomide and capecitabine regimen (decrease in tumor size of 70% with RECIST criteria). Tumor cells harbored a new mutation in SDHB gene and showed aberrant hypermethylation of O6-methylguanine-DNA-methyltransferase promoter. Our report suggests the importance of molecular predictive factors of response for the selection of chemotherapeutic as well as targeted agents. This observation points to a possible genotype response to treatment relationships, which could help to design tailor-made treatments in the future.     

K40E: a novel succinate dehydrogenase (SDH)B mutation causing familial phaeochromocytoma and paraganglioma

OBJECTIVE: Germline mutations in succinate dehydrogenase (SDH)B, SDHC and SDHD, encoding three of the four subunits of mitochondrial complex II, have been implicated in the tumourigenesis of familial paragangliomas and phaeochromocytomas. Twenty-three SDHB mutations have been identified to date. PATIENTS: We present a novel missense SDHB exon 2 mutation (c.118 A > G; K40E) identified in an Australian family. The proband was diagnosed with phaeochromocytoma at an early age following an unexpected hypertensive crisis and was found to be SDHB mutation-positive. Subsequent genetic screening of 26 family members has identified 17 mutation-positive relatives. In addition to the proband, four mutation positive relatives were found to have clinical symptoms or a lesion and/or catecholamine excess after the identification of the mutation led to further evaluation. Both the proband and an uncle have required surgical removal of a tumour. CONCLUSIONS: This family indicates the importance of germline screening of first-degree relatives when a patient presents with an apparently sporadic extra adrenal phaeochromocytoma at a young age or whenever a patient with a nonsecretory paraganglioma is found.