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Abstract：
Object Exclusively dopamine-producing pheochromocytoma/paraganglioma (PPGL) is an extremely rare subtype. In this condition, intratumoral dopamine β-hydroxylase (DBH), which controls the conversion of norepinephrine from dopamine, is impaired, resulting in suppressed norepinephrine and epinephrine production. However, the rarity of this type of PPGL hampers the understanding of its pathophysiology. We therefore conducted genetic and immunohistological analyses of a patient with an exclusively dopamine-producing paraganglioma. Methods Paraganglioma samples from a 52-year-old woman who presented with a 29.6- and 41.5-fold increase in plasma and 24-h urinary dopamine, respectively, but only a minor elevation in the plasma norepinephrine level was subjected to immunohistological and gene expression analyses of catecholamine synthases. Three tumors carrying known somatic PPGL-related gene variants (HRAS, EPAS1) were used as controls. Whole-exome sequencing (WES) was also performed using the patient\'s blood and tumor tissue. Results Surprisingly, the protein expression of DBH was not suppressed, and its mRNA expression was clearly higher in the patient than in the controls. Furthermore, dopa decarboxylase (DDC), which governs the conversion of 3,4-dihydroxyphenyl-L-alanine (L-DOPA) to dopamine, was downregulated at the protein and gene levels. In addition, melanin, which is synthesized by L-DOPA, accumulated in the tumor. WES revealed no PPGL-associated pathogenic germline variants, but a missense somatic variant (c.1798G>T) in CSDE1 was identified. Conclusion Although pre-operative plasma L-DOPA was not measured, our histological and gene expression analyses suggest that L-DOPA, rather than dopamine, might have been overproduced in the tumor. This raises the possibility of pathophysiological heterogeneity in exclusively dopamine-producing PPGL.
摘要：
目的仅产生多巴胺的嗜铬细胞瘤/副神经节瘤（PPGL）是一种极为罕见的亚型。在这种情况下,肿瘤内多巴胺β-羟化酶（DBH），控制多巴胺中去甲肾上腺素的转化，受损，导致抑制去甲肾上腺素和肾上腺素的产生。然而,这种类型的PPGL的稀有性阻碍了对其病理生理学的理解。因此，我们对患有仅产生多巴胺的副神经节瘤的患者进行了遗传和免疫组织学分析。方法和患者来自52岁女性的副神经节瘤样本，该女性的血浆和24小时尿多巴胺增加29.6倍和41.5倍，分别,但是，只有血浆去甲肾上腺素水平略有升高，才进行了儿茶酚胺合酶的免疫组织学和基因表达分析。三种携带已知体细胞PPGL相关基因变异的肿瘤(HRAS，EPAS1）用作对照。还使用患者的血液和肿瘤组织进行全外显子组测序(WES)。结果令人惊讶,DBH的蛋白表达没有被抑制，患者的mRNA表达明显高于对照组。此外，多巴脱羧酶（DDC），控制3,4-二羟苯基-1-丙氨酸（1-DOPA）向多巴胺的转化，在蛋白质和基因水平下调。此外,黑色素,它是由l-DOPA合成的，积聚在肿瘤中。WES未显示PPGL相关致病性种系变异，但在CSDE1中发现了一个错义的体细胞变异(c.1798G>T)。结论虽然术前血浆L-DOPA没有测定,我们的组织学和基因表达分析表明L-DOPA，而不是多巴胺，可能在肿瘤中过度产生。这增加了仅产生多巴胺的PPGL的病理生理异质性的可能性。
