Metastatic cluster 2-related pheochromocytoma/paraganglioma: a single-center experience and systematic review.

Objective Risk of metastatic disease in the cluster 2-related pheochromocytoma/paraganglioma (PPGL) is low. In MEN2 patients, identification of origin of metastases from pheochromocytoma (PCC) or medullary thyroid carcinoma (MTC) is challenging as both are of neuroendocrine origin. We aim to describe our experience and perform a systematic review to assess prevalence, demographics, biochemistry, diagnostic evaluation, management and predictors of cluster 2-related metastatic PPGL. Design Retrospective study with systematic review of literature. Methods Data of 3 cases from our cohort and 43 cases from world literature were analyzed. For calculation of prevalence, all reported patients (n=3063) of cluster 2 were included. Results The risk of metastasis in cluster 2-related PPGL was 2.6% (2% in RET, 5% in NF1, 4.8% in TMEM127 and 16.7% in MAX variation). In metastatic PCC in MEN2, median age was 39 years, bilateral tumors were present in 71% and median tumor size was 9.7 cm (range 4-19) with 43.5% mortality. All patients had primary tumor size ≥4cm. Origin of primary was diagnosed by histopathology of metastatic lesion in 11(57.9%), 131I-MIBG scan in 6(31.6%), and selective venous sampling and computed tomography in one (5.3%) each. In subgroup of NF1, median age was 46 years (range 14-59) with median tumor size 6cm and 57% mortality. Conclusion The risk of metastatic disease in cluster 2-related PPGL is 2.6%, being especially high in tumors with size ≥4cm and is associated with high mortality. One-third patients of NF1 with metastatic PPGL had presented in 2nd decade of life. Long-term studies are needed to formulate management recommendations.