Lack of utility of SDHB mutation testing in adrenergic metastatic phaeochromocytoma

Abstract

Objective: Testing for succinate dehydrogenase subunit B (SDHB) mutations is recommended in all patients with metastatic phaeochromocytomas and paragangliomas (PPGLs), but may not be required when metastatic disease is accompanied by adrenaline production. This retrospective cohort study aimed to establish the prevalence of SDHB mutations among patients with metastatic PPGLs, characterised by production of adrenaline compared with those without production of adrenaline, and to establish genotype-phenotype features of metastatic PPGLs according to underlying gene mutations. Design and methods: Presence of SDHB mutations or deletions was tested in 205 patients (114 males) aged 42G16 years (range 9-86 years) at diagnosis of metastatic PPGLs with and without adrenaline production. Results: Twenty-three of the 205 patients (11%) with metastatic PPGLs had disease characterised by production of adrenaline, as defined by increased plasma concentrations of metanephrine larger than 5% of the combined increase in both normetanephrine and metanephrine. None of these 23 patients had SDHB mutations. Of the other 182 patients with no tumoural adrenaline production, 51% had SDHB mutations. Metastases in bone were 36-41% more prevalent among patients with SDHB mutations or extra-adrenal primary tumours than those without mutations or with adrenal primary tumours. Liver metastases were 81% more prevalent among patients with adrenal than extra-adrenal primary tumours. Conclusion: SDHB mutation testing has no utility among patients with adrenaline-producing metastatic PPGLs, but is indicated in other patients with metastatic disease. Our study also reveals novel associations of metastatic spread with primary tumour location and presence of SDHB mutations.

Multimodal Somatostatin Receptor Theranostics Using [64Cu]Cu-/[177Lu]Lu-DOTA-(Tyr3)octreotate and AN-238 in a Mouse Pheochromocytoma Model

“…This is also in agreement with other findings of high SSTR2 expression in PHEO/PGLs due to SDHB mutations 61 . These clinical findings support the possibility that utility of [ 177 Lu]Lu-DOTATATE reported here in the MPC-mCherry model may indeed translate to the clinic, and particularly to metastatic PHEO/PGLs due to SDHB mutations, which carry a high metastatic risk responsible for 40-50% of all cases of malignant disease 62 , 63 .…”

Recent Advances in Histopathological and Molecular Diagnosis in Pheochromocytoma and Paraganglioma: Challenges for Predicting Metastasis in Individual Patients

“…PNMT catalyzes the final step of catecholamine biosynthesis from norepinephrine into epinephrine. Of particular interest, pseudohypoxic PPGLs are generally negative for PNMT, and have silent clinical and hormonal phenotypes, which could delay therapeutic intervention in such patients (93). Fukaya et al reported that lower DDC immunoreactivity was detected in poorly differentiated PPGLs, histologically representing confluent necrosis, diffuse growth, nuclear polymorphism, and tumor cell spindling (94).…”

Intricacies of the Molecular Machinery of Catecholamine Biosynthesis and Secretion by Chromaffin Cells of the Normal Adrenal Medulla and in Pheochromocytoma and Paraganglioma

“…In a relatively large series of patients with metastatic PPGL, only a minority (11%) of patients had an adrenergic phenotype. Of note, none of these patients had a SDHB -related pheochromocytoma or paraganglioma [240]. The biochemical profile has also been linked to prognosis, as it was shown that patients with elevated plasma levels of dopamine and norepinephrine had a faster progression of their disease [239].…”