Molecular and Therapeutic Advances in the Diagnosis and Management of Malignant Pheochromocytomas and Paragangliomas

Abstract

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare catecholamine-secreting tumors derived from chromaffin cells originating in the neural crest. These tumors represent a significant diagnostic and therapeutic challenge because the diagnosis of malignancy is frequently made in retrospect by the development of metastatic or recurrent disease. Complete surgical resection offers the only potential for cure; however, recurrence can occur even after apparently successful resection of the primary tumor. The prognosis for malignant disease is poor because traditional treatment modalities have been limited. The last decade has witnessed exciting discoveries in the study of PCCs and PGLs; advances in molecular genetics have uncovered hereditary and germline mutations of at least 10 genes that contribute to the development of these tumors, and increasing knowledge of genotype-phenotype interactions has facilitated more accurate determination of malignant potential. Elucidating the molecular mechanisms responsible for malignant transformation in these tumors has opened avenues of investigation into targeted therapeutics that show promising results. There have also been significant advances in functional and radiological imaging and in the surgical approach to adrenalectomy, which remains the mainstay of treatment for PCC. In this review, we discuss the currently available diagnostic and therapeutic options for patients with malignant PCCs and PGLs and detail the molecular rationale and clinical evidence for novel and emerging diagnostic and therapeutic strategies. TheOncologist2013; 18:391-407 Implications for Practice: Malignant pheochromocytoma and paraganglioma represent a significant management challenge.The diagnosis of malignancy is frequently made in retrospect and traditional treatment modalities have been limited. Recent exciting advances in molecular genetics have uncovered hereditary and germline mutations of at least 10 genes that contribute to the development of these tumors. Increasing knowledge of genotype-phenotype interactions facilitates more accurate determination of malignant potential and has prompted investigation into targeted therapeutics with promising results. There have also been significant advances in functional and radiological imaging and in the surgical approach to adrenalectomy, which remains the mainstay of treatment for pheochromocytoma. Due to the rarity of this tumor, large-scale clinical studies that would progress clinical practice are rare, and the requirement for international collaboration is crucial. The need for large-scale international multicenter studies to effectively exploit the molecular and genetic knowledge gained in this area is highlighted in this review.

Metastatic phaeochromocytoma in a 23‐year‐old woman with an unclassified variant in the von Hippel Lindau disease gene: how can the pathogenicity of this variant be determined?

“…Histological examination confirmed a left adrenal PCC. The Ki67 index was 8–10% and the phaeochromocytoma of the Adrenal Gland Scaled Score (PASS) was 5/20, predicting malignant behaviour . This was confirmed by the finding of metastatic PCC in the liver specimen.…”

Paraganglioma with Hyperglycaemia as the Main Symptom: A Case Report.

“…Some studies have shown that Hif-2α inhibitors, Everolimus, Sunitinib and other drugs, can be used for the effective treatment of the disease. [12][13][14] In this study, the patient had hyperglycaemia in the early stage of the course of the disease, and she was resultantly misdiagnosed with type 2 diabetes mellitus. The clinician used a variety of hypoglycaemic drugs to try to control the patient's blood glucose level, but these drugs were unsuccessful.…”

MicroRNAs used as novel biomarkers for detecting cancer metastasis

“…A single miRNA can regulate the expression of hundreds of downstream genes, which has a broad effect on the regulation of the whole cell cycle. It is revealed that miRNAs are involved in cellular proliferation, apoptosis, differentiation, metabolism, and other cellular processes [8]. MiRNAs play important roles in transcription or posttranscription level by specific pairing with the 3′ UTR of the target messenger RNA (mRNA), leading mRNA activation inhibition or degradation of target mRNA.…”