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

Abstract

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.

A case of malignant pheochromocytoma with neurofibromatosis type 1 having difficulty in differentiating spinal tumor

“…1,3 A previous report detailed 10 cases of metastatic pheochromocytoma associated with NF1, with a median age of 46 years and median tumor size of 6 cm. 13 The most common site of metastasis was the bone (50%), followed by the lung and liver, 13 as with general malignant pheochromocytoma. 6 NF1 is often associated with bone involvement, which is important in differentiating it from bone metastasis.…”

“…Pheochromocytomas manifest in 0.1%–5.7% of patients with NF1, 3 with a rate of malignant transformation comparable to general malignant pheochromocytomas 1,3 . A previous report detailed 10 cases of metastatic pheochromocytoma associated with NF1, with a median age of 46 years and median tumor size of 6 cm 13 . The most common site of metastasis was the bone (50%), followed by the lung and liver, 13 as with general malignant pheochromocytoma 6 …”

Tumor metabolism in pheochromocytomas: clinical and therapeutic implications

“…Likewise, RET, TMEM127, and MAX gene mutations have been implicated in perturbed cellular signaling, highlighting the kinase-signaling cluster’s instrumental role in comprehending PPGL tumor characteristics [ 38 , 42 , 54 ]. Similar to cluster 1 disease, cluster 2 disease has been further divided into subclusters: cluster 2A (presenting mutations in RET, NF1, and TMEM127 ), cluster 2B (sporadic tumors), and cluster 2C (displaying mutations in VHL 3.7% and RET 11.1%, plus sporadic tumors) [ 55 , 56 ].…”

Identification of potential molecular targets for the treatment of cluster 1 human pheochromocytoma and paraganglioma via comprehensive proteomic characterization

“…Cluster 2 PPGLs (roughly 50–60% of all PPGLs) comprise tumors harboring pathogenic variants in genes associated with tyrosine-kinase signaling ( RET , NF1 , HRAS , TMEM127 , MAX , FGFR1 , MET , MERTK , BRAF and NGFR ). Cluster 2 PPGLs present frequently as bilateral pheochromocytomas which are not highly prone to metastatic progression (metastatic risk ranges between 2 and 11%) [ 4 ].…”