Synchronous Malignant Pheochromocytoma With Renal Cell Carcinoma: A Case Report

Introduction: In the US, Pheochromocytoma/paraganglioma incidence is estimated to be 2–8 per 1 million people each year with around 100–200 of these cases being malignant. Malignant pheochromocytoma is defined by documented presence of metastases or evidence of extensive local invasion. There are certain genetic syndromes which are also associated with renal cell carcinoma, including SDHB mutations type 4, VHL disease and familial pheochromocytoma. These syndromes are important to recognize as they may signify a worse prognosis. Here, we describe a case of co-occurrence of malignant PC with renal cell carcinoma. Case Report: A 53-year-old Hispanic male with history of HTN and recently diagnosed metastatic pheochromocytoma was admitted for surgical debulking of the left retroperitoneal/adrenal and renal masses. Symptoms began five months prior after he presented with an ischemic stroke in the setting of labile hypertension. He was diagnosed with a 6.3 x 4.6 x 6.8 cm incidental left retroperitoneal mass and suspicious left renal mass on CT imaging but also noted several lytic bony lesions concerning for bone metastasis. A spinal biopsy was obtained which was consistent with a well-differentiated metastatic neuroendocrine tumor. Laboratory evaluation was notable for Chromogranin A level of 6959ng/mL (25–140). He was started on Lanreotide. Given persistently difficult to control HTN he underwent work up for secondary hypertension. Hormonal evaluation was notable for plasma free metanephrine of 534pg/mL (<57pg/mL), normetanephrine 6155pg/mL(<148pg/mL), and total metanephrine of 6689pg/mL (205pg/mL) consistent with metastatic Pheochromocytoma. After appropriate alpha blockade he underwent left adrenalectomy, nephrectomy and liver tumor microwave ablation. Pathology was consistent with an 8.7cm pheochromocytoma with extensive retroperitoneal soft tissue invasion and PASS score of 9 as well as a 3.6 cm renal cell (clear cell-papillary type) carcinoma. On follow up, Plasma metanephrine decreased significantly postoperatively to a free metanephrine of 28pg/ml, normetanephrine 1153pg/ml, and total metanephrine of 1181pg/mL. He was referred for genetic testing but unfortunately, he was readmitted one month later with cerebral hemorrhage and expired. Conclusion: Advancements in genetics have led to improved understanding of the molecular etiologies of pheochromocytomas. A number of genetic defects are associated with PC and RCC, including SDHB mutations type 4, VHL and familial pheochromocytoma. Our case underscores the high morbidity and mortality in patients with metastatic PC with RCC and perhaps the catastrophic outcomes in such patients. Assessing patient’s genetics in these cases is now the standard of care, however further research studies are warranted to better understand the significance of tumor genetics on prognosis and management.

Bilateral Familial Pheochromocytoma: Difficulty of Diagnosis and Management

Introduction: Bilateral pheochromocytoma is a rare tumor, often seen in the context of a family illness. The majority of pheochromocytomas are sporadic, but they can also occur within the framework of genetic diseases (10%): MEN2, VPL, NF1, familial paraganglioma (mutation of SDHB)⋯ In the context of a familial genetic disease, the pheochromocytoma can be either unilateral or bilateral, benign in 95% of cases and malignant in 5%. It still poses several problems related to its diagnosis, genetic aspects, especially in the absence of a family history. And the criteria of malignancy, given the non-existence to date of a certain & universal criterion that judges the malignancy of the tumor. We present through this article the exceptional case of “bilateral familial pheochromocytomas with strong suspicion of malignancy”. Clinical Case: A 29-year-old lady, hypertensive since 4 years, admitted for exploration of severe secondary hypertension. She reports a triad of menard and severe lumbar pain, the somatic examination shows hypersensitivity of the flanks, a BP of 240/120 mmhg. the abdominal CT scan confirmed by an MRI show a right adrenal mass of 5 cm & another left of 1 cm, of suspicious appearance (irregular contours, areas of necrosis, heterogeneity, spontaneous density at 35 HU, a wash out at 33% with presence of L4 spinal angioma and peri-aortic lymph nodes. urinary methoxylated derivatives (UMD) returned high. The genetic study was positive VPL (on various radiological tests, there was just a spinal angioma) We retained the diagnosis of familal bilateral pheochromocytoma. In front of the clinical & radiological signs of malignancy, we decided to do: a right total adrenalectomy & a left partial adrenalectomy. Unfortunately, the blood pressure didn’t drop, and UMD were still positive; the anatomopathological study shows a pheochromocytoma with a PASS score estimated at 3 (benign!) Faced with conflicting clinical-radiological and histological data, we decided to total adrenalectomy without lymph node dissection and to closely monitor the progress. the post Op blood pressure was normalized and the UMD returned negative. Conclusion: Malignant familial bilateral pheochromocytoma is a very rare & very difficult entity to diagnose, manage & monitor. A good management requires serious collaboration between: endocrinologist, radiologist, urologist, pathologist

ANAESTHETIC MANAGEMENT OF A CASE OF PHEOCHROMOCYTOMA - A CASE REPORT

Pheochromocytoma is a rare catecholamine secreting tumour originating usually from adrenal medulla and produces [4,5] [4] signs and symptoms due to excessive catecholamine secretion. Pheochromocytoma is called '10% tumour' because 10 percent are bilateral, malignant, extra-adrenal, multiple and familial. Pheochromocytoma is one of [4] the few causes of hypertension that can be treated surgically. Detection is mandatory for the potential cure of hypertension and to avoid the lethal effects. Pheochromocytoma has an overall good prognosis, with a 5-year [5] survival greater than 95% in benign tumours and recurrences below 10% for malignant tumours.

SAT-186 Metastatic Paraganglioma Secondary to SDHB Gene Mutation: A Case Report and Review of New Therapies

Background: Paragangliomas (PGL) are rare neuroendocrine tumors that arise from the extra-adrenal autonomic paraganglia, majority of which are benign. 0-36% of PGL patients can develop metastatic disease, depending on the genetic mutation. We present a case of a patient with metastatic PGL due to an SDHB gene mutation. We then summarize published and ongoing trials of therapies for metastatic pheochromocytoma/PGL. Clinical Case: A 54 years old male presented to the Emergency Department with severe left lower quadrant pain. He additionally reported recent episodes of headaches and uncontrolled hypertension, as well as an approximate weight loss of 50 pounds in the preceding two years. A CT abdomen and pelvis demonstrated an 8 cm left peri-aortic retroperitoneal mass, along with a 2 cm solitary hepatic lesion concerning for metastatic disease. Normetanephrine levels were elevated at 1210 pg/mL (normal 0-145 pg/mL). Endoscope-guided biopsy of the retroperitoneal mass demonstrated findings consistent with a PGL. The patient was referred to a genetic counsellor where he underwent PGLNext testing. He tested positive for a c.418G>T mutation in the SDHB gene, consistent with a diagnosis of hereditary paraganglioma - pheochromocytoma (PGL-Pheo) syndrome. Patient was planned for surgical debulking of his PGL, and was treated pre-operatively with Phenoxybenzamine, followed by B-blockers. He underwent resection of the retroperitoneal mass and wedge resection of the hepatic mass. Surgical pathology revealed a 10.5 cm extra adrenal PGL and a 2 cm metastatic PGL involving the liver with negative margins of resection. Patient did well in the post-operative period, and was discharged with plans to repeat plasma metanephrines in 6-8 weeks. The patient was referred to the National Cancer Institute (NCI) for enrollment in a clinical trial using Lu-177-DOTATATE. Conclusion: Though rare, pheochromocytomas (pheo) and PGL can be lethal if not diagnosed and managed appropriately. As of 2019, at least 19 genes have been identified that predispose to familial pheochromocytoma/PGL. Importantly, PGL that are associated with SDHB, the mutation our patient had, are more likely to appear in the abdomen (rather than the head and neck), are usually secretory (most commonly norepinephrine) and are more likely to become metastatic (21-79%). Patients with metastatic pheo/PGL require complex care in specialized centers by a multidisciplinary team of specialists. Patients with advanced or non-resectable metastatic pheo/PGL should preferably be offered a referral to NCI or an NCI designated cancer center for enrollment in a clinical trial of targeted therapies.

Germline variant in REXO2 is a novel candidate gene in familial pheochromocytoma

Pheochromocytoma (PCC) is a rare, mostly benign tumour of the adrenal medulla. Hereditary PCC accounts for ~35% of cases and has been associated with germline mutations in several cancer susceptibility genes (e.g., KIF1B, SDHB, VHL, SDHD, RET). We performed whole-exome sequencing in a family with four PCC-affected patients in two consecutive generations and identified a potential novel candidate pathogenic variant in the REXO2 gene that affects splicing (c.531-1G>T (NM 015523.3)), which co-segregated with the phenotype in the family. REXO2 encodes for RNA exonuclease 2 protein and localizes to 11q23, a chromosomal region displaying allelic imbalance in PCC. REXO2 protein has been associated with DNA repair, replication and recombination processes and thus its inactivation may contribute to tumorigenesis. While the study suggests that this novel REXO2 gene variant underlies PCC in this family, additional functional studies are required in order to establish the putative role of the REXO2 gene in PCC predisposition.

EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance

Despite the discovery of the oxygen-sensitive regulation of HIFα by the von Hippel–Lindau (VHL) protein, the mechanisms underlying the complex genotype/phenotype correlations in VHL disease remain unknown. Some germline VHL mutations cause familial pheochromocytoma and encode proteins that preserve their ability to down-regulate HIFα. While type 1, 2A, and 2B VHL mutants are defective in regulating HIFα, type 2C mutants encode proteins that preserve their ability to down-regulate HIFα. Here, we identified an oxygen-sensitive function of VHL that is abolished by VHL type 2C mutations. We found that BIM-EL, a proapoptotic BH3-only protein, is hydroxylated by EglN3 and subsequently bound by VHL. VHL mutants fail to bind hydroxylated BIM-EL, regardless of whether they have the ability to bind hydroxylated HIFα or not. VHL binding inhibits BIM-EL phosphorylation by extracellular signal-related kinase (ERK) on serine 69. This causes BIM-EL to escape from proteasomal degradation, allowing it to enhance EglN3-induced apoptosis. BIM-EL was rapidly degraded in cells lacking wild-type VHL or in which EglN3 was inactivated genetically or by lack of oxygen, leading to enhanced cell survival and chemotherapy resistance. Combination therapy using ERK inhibitors, however, resensitizes VHL- and EglN3-deficient cells that are otherwise cisplatin-resistant.

Synonymous but Not Silent: A Synonymous VHL Variant in Exon 2 Confers Susceptibility to Familial Pheochromocytoma and von Hippel-Lindau Disease

Context von Hippel-Lindau (VHL) disease, comprising renal cancer, hemangioblastoma, and/or pheochromocytoma (PHEO), is caused by missense or truncating variants of the VHL tumor-suppressor gene, which is involved in degradation of hypoxia-inducible factors (HIFs). However, the role of synonymous VHL variants in the disease is unclear. Objective We evaluated a synonymous VHL variant in patients with familial PHEO or VHL disease without a detectable pathogenic VHL mutation. Design We performed genetic and transcriptional analyses of leukocytes and/or tumors from affected and unaffected individuals and evaluated VHL splicing in existing cancer databases. Results We identified a synonymous VHL variant (c.414A>G, p.Pro138Pro) as the driver event in five independent individuals/families with PHEOs or VHL syndrome. This variant promotes exon 2 skipping and hence, abolishes expression of the full-length VHL transcript. Exon 2 spans the HIF-binding domain required for HIF degradation by VHL. Accordingly, PHEOs carrying this variant display HIF hyperactivation typical of VHL loss. Moreover, other exon 2 VHL variants from the The Cancer Genome Atlas pan-cancer datasets are biased toward expression of a VHL transcript that excludes this exon, supporting a broader impact of this spliced variant. Conclusion A recurrent synonymous VHL variant (c.414A>G, p.Pro138Pro) confers susceptibility to PHEO and VHL disease through splice disruption, leading to VHL dysfunction. This finding indicates that certain synonymous VHL variants may be clinically relevant and should be considered in genetic testing and surveillance settings. The observation that other coding VHL variants can exclude exon 2 suggests that dysregulated splicing may be an underappreciated mechanism in VHL-mediated tumorigenesis.