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


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          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. Retrospective analysis of 3 cases from our cohort and 43 cases from world literature was done. For calculation of prevalence, all reported patients ( n = 3063) of cluster 2 were included. We found that 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 a primary tumor size ≥4 cm. Origin of primary tumor was diagnosed by histopathology of metastatic lesion in 11 (57.9%), 131I-MIBG scan in 6 (31.6%), and selective venous sampling and CT in 1 (5.3%) patient each. In subgroup of neurofibromatosis 1 (NF1), median age was 46 years (range 14–59) with median tumor size 6 cm and 57% mortality. To conclude, the risk of metastatic disease in cluster 2-related PPGL is low, being especially high in tumors with size ≥4 cm and associated with high mortality. One-third patients of NF1 with metastatic PPGL had presented in second decade of life. Long-term studies are needed to formulate management recommendations.

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          Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.

          The aim was to formulate clinical practice guidelines for pheochromocytoma and paraganglioma (PPGL).
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            Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma.

            Hereditary pheochromocytoma (PCC) is often caused by germline mutations in one of nine susceptibility genes described to date, but there are familial cases without mutations in these known genes. We sequenced the exomes of three unrelated individuals with hereditary PCC (cases) and identified mutations in MAX, the MYC associated factor X gene. Absence of MAX protein in the tumors and loss of heterozygosity caused by uniparental disomy supported the involvement of MAX alterations in the disease. A follow-up study of a selected series of 59 cases with PCC identified five additional MAX mutations and suggested an association with malignant outcome and preferential paternal transmission of MAX mutations. The involvement of the MYC-MAX-MXD1 network in the development and progression of neural crest cell tumors is further supported by the lack of functional MAX in rat PCC (PC12) cells and by the amplification of MYCN in neuroblastoma and suggests that loss of MAX function is correlated with metastatic potential.
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              New Perspectives on Pheochromocytoma and Paraganglioma: Toward a Molecular Classification.

              A molecular biology-based taxonomy has been proposed for pheochromocytoma and paraganglioma (PPGL). Data from the Cancer Genome Atlas revealed clinically relevant prognostic and predictive biomarkers and stratified PPGLs into three main clusters. Each subgroup has a distinct molecular-biochemical-imaging signature. Concurrently, new methods for biochemical analysis, functional imaging, and medical therapies have also become available. The research community now strives to match the cluster biomarkers with the best intervention. The concept of precision medicine has been long awaited and holds great promise for improved care. Here, we review the current and future PPGL classifications, with a focus on hereditary syndromes. We discuss the current strengths and shortcomings of precision medicine and suggest a condensed manual for diagnosis and treatment of both adult and pediatric patients with PPGL. Finally, we consider the future direction of this field, with a particular focus on how advanced molecular characterization of PPGL can improve a patient's outcome, including cures and, ultimately, disease prevention.

                Author and article information

                Endocr Connect
                Endocr Connect
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                18 October 2021
                01 November 2021
                : 10
                : 11
                : 1463-1476
                [1 ]Department of Endocrinology , Seth G S Medical College & KEM Hospital, Mumbai, India
                [2 ]Department of Endocrinology , Vydehi Institute of Medical Sciences and Research Centre, Bangalore, India
                [3 ]Department of Pathology , Tata Memorial Hospital, Mumbai, India
                [4 ]Department of Uro-oncology , Tata Memorial Hospital, Mumbai, India
                [5 ]Department of Nuclear Medicine , Bhabha Atomic Research Centre, Mumbai, India
                Author notes
                Correspondence should be addressed to T R Bandgar: drtusharb@ 123456gmail.com
                Author information
                © The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

                : 28 September 2021
                : 18 October 2021

                metastatic pheochromocytoma,men2a,men2b,nf1,cluster 2
                metastatic pheochromocytoma, men2a, men2b, nf1, cluster 2


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