A Multicenter Epidemiological Study on Second Malignancy in Non-Syndromic Pheochromocytoma/Paraganglioma Patients in Italy.

Letizia Canu,Uberta Verga,Antonio Concistrè,Giuseppe Reimondo,Luigi Petramala,Stefania Zovato,Alfonso Massimiliano Ferrara,Tonino Ercolino,Francesca Brignardello,Anna Pia,Jacopo Burrello,Giuseppe Opocher,Massimo Terzolo,Barbara Altieri,Mario Maggi,Marialuisa Appetecchia,Michaela Luconi,Antongiulio Faggiano,Emanuela Arvat,Micaela Pellegrino,Mauro Maccario,Roberta Modica,Antonio Stigliano,Soraya Puglisi,Paola Berchialla,Francesca Schiavi,Valentina Morelli,Massimo Mannelli,Elena Rapizzi,Mirko Parasiliti-Caprino,Maura Arosio,Giuseppina De Filpo,Claudio Letizia,Paola Razzore

doi:10.3390/cancers13225831

Abstract

Simple SummaryAs no previous studies had assessed the risk of second malignant tumors in patients with pheochromocytomas/paragangliomas (PPGLs), we aimed to evaluate whether these patients could have an increased risk of additional malignancy, comparing them with patients in the general population who had a first malignancy and developed a second malignant tumor. We demonstrated that PPGL patients had higher incidence of additional malignant tumors and the risk of developing a second malignant tumor increased with age at diagnosis. As the main tumors were prostate, colorectal and lung/bronchial cancers in males, and breast cancer, differentiated thyroid cancer and melanoma in females, our findings could have an impact on the surveillance strategy.No studies have carried out an extensive analysis of the possible association between non-syndromic pheochromocytomas and paragangliomas (PPGLs) and other malignancies. To assess >the risk of additional malignancy in PPGL, we retrospectively evaluated 741 patients with PPGLs followed-up in twelve referral centers in Italy. Incidence of second malignant tumors was compared between this cohort and Italian patients with two subsequent malignancies. Among our patients, 95 (12.8%) developed a second malignant tumor, which were mainly prostate, colorectal and lung/bronchial cancers in males, breast cancer, differentiated thyroid cancer and melanoma in females. The standardized incidence ratio was 9.59 (95% CI 5.46–15.71) in males and 13.21 (95% CI 7.52–21.63) in females. At multivariable analysis, the risk of developing a second malignant tumor increased with age at diagnosis (HR 2.50, 95% CI 1.15–5.44, p = 0.021 for 50–59 vs. <50-year category; HR 3.46, 95% CI 1.67–7.15, p < 0.001 for >60- vs. <50-year). In patients with available genetic evaluation, a positive genetic test was inversely associated with the risk of developing a second tumor (HR 0.25, 95% CI 0.10–0.63, p = 0.003). In conclusion, PPGLs patients have higher incidence of additional malignant tumors compared to the general population who had a first malignancy, which could have an impact on the surveillance strategy.

Highlights

Pheochromocytomas and paragangliomas (PPGLs) are rare tumors arising from the neural crest [1]
The analysis revealed an association with age
In females we found that the most frequent cancers associated with pheochromocytomas and paragangliomas (PPGLs) were breast cancer, differentiated thyroid cancer (DTC) and melanoma

Summary

Introduction

Pheochromocytomas and paragangliomas (PPGLs) are rare tumors arising from the neural crest [1]. Until a few years ago, the association of PPGL with other solid tumors was reported only in neurofibromatosis type 1 (NF1), multiple endocrine neoplasia type 2 (MEN2) and von Hippel Lindau (VHL) syndrome. Non-chromaffin tumors have recently been reported in patients with PPGL without any of these syndromic diseases. SDHx mutations have been associated with renal cell carcinomas (RCCs) [5], gastrointestinal stromal tumors (GISTs) [6,7] and pituitary adenomas (PAs) [6]. SDHx mutated RCCs represent less than 0.5% of all renal carcinomas [8], whereas 30% of GISTs are associated with SDHA mutations [9]

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