Genetic Study in Pheochromocytoma: Is It Possible to Stratify the Risk of Hereditary Pheochromocytoma?

Abstract

Introduction: It is estimated that 30-40% of patients with apparently sporadic pheochromocytomas (PHEOs) have an inherited predisposition syndrome. The aim of our study was to develop a predictive model of hereditary pheochromocytoma (PHEO) based on the clinical, hormonal, and radiological features present at the diagnosis of patients with PHEOs. Methods: A retrospective multicenter cohort study of patients with PHEOs with available genetic study from 18 tertiary hospitals. Clinical, biochemical, and radiological features were used to build a multivariate logistic regression model. The estimation of all possible equations was used to select the model with the best diagnostic accuracy (lower Akaike index (AIC)). Results: A total of 245 patients were included: 169 (69.0%) patients with sporadic PHEOs and 76 (31%) with hereditary PHEOs. The parsimonious predictive model with the highest diagnostic accuracy for the prediction of hereditary PHEO combined the variables age, non-cardiovascular disease, urinary norepinephrine levels and tumor size. The area under the ROC curve of this model was of 0.800 (0.705-0.887). Based on the predictive model, the probability of hereditary PHEO in patients older than 60 years with cardiovascular disease, high levels of urinary norepinephrine and unilateral PHEOs >60 mm was <2%. And if the age was above 80 years, lower than 1%. The probability of sporadic PHEO linearly increased with age (MH Test for linear Trend: Chi2(1) = 30.05; P<0.001) Conclusion: In certain populations such as old patients with cardiovascular disease, with high levels of urinary norepinephrine and large tumors in which the probability of hereditary PHEO is very low, genetic testing could be avoided in the absence of specific suspicion

Differences between Patients with Sporadic and Familial Pheochromocytoma—Is It Possible to Avoid Genetic Testing in Certain Patients?

“…The overall percentage of familial PHEO in our study rises to 64.71%, one of the highest prevalence rates in the literature. In a recent study published by Araujo-Castro et al in which only PHEO was taken into account and PGL was excluded, the percentage of familial PHEO was 31%, even using a broader panel than ours that included 25 genes [ 4 ]. The predominant gene in our series was the proto-oncogene RET for MEN 2A, representing 86.36% of the 88 patients with a positive mutation, as there is a high prevalence of this syndrome in our geographical area.…”

“…The study, which was published by Ma et al, included seven patients with a mutation in SDHA , but only one developed a PHEO, and the rest were PGL. In the study of Araujo-Castro et al, there is also a case of PHEO with a mutation in SDHA [ 4 , 20 ].…”

“…PHEO is the solid tumour with the greatest genetic predisposition, being the most frequent mutation in Von Hippel Lindau ( VHL ). For this reason, it is recommended that all patients undergo genetic screening [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ].…”

Local recurrence and metastatic disease in pheochromocytomas and sympathetic paragangliomas

“…A Spanish multicentric retrospective study of patients who underwent surgical resection of a PPGL between 1998 and 2022 in 19 tertiary hospitals was carried out. As we have previously described ( 18 ), the following criteria should be met to enter in the PHEO-PARA risk study: i) an age at diagnosis of the PPGL older than 17 years old; ii) histological diagnostic confirmation of PPGL, iii) available clinical, biochemical, and radiological information at the diagnosis of the PPGL and during follow-up and iv) absence of evidence of metastatic disease at the time of the diagnosis. Among all patients, 303 patients with PPGLs who underwent to 311 resections met the inclusion criteria and were included (288 pheochromocytomas and 15 sympathetic PGLs) ( Figure 1 ).…”

“…Hereditary PPGL diagnosis was based on the presence of a pathogenic germline variant in known susceptibility genes. As we have previously described ( 18 ), in all patients with a negative genetic study, at least the following genes have been sequenced: NF1, RET, VHL, SDHA, SDHB, SDHC , and SDHD. In addition, most of the centers tested also other genes, including SDHAF2, SDHAF1, MAX, HIF1A, HIF2A, TMEM127, HRAS, KRAS, GOT2, FH, MDH2, SLC25A11, DNMT3A, DLST, MERTK, IDH1, IDH2, CSED1, EGLN1, EGLN2, BRAF, MET, FGFR1, KIF1B,CDKN1B, MEN1, PTEN, H3F3a, ATRX , and the promoter region of TER.…”