Composite pheochromocytoma/paraganglioma-ganglioneuroma: analysis of SDH and ATRX status and identification of frequent HRAS and BRAF mutations

Introduction: Composite pheochromocytoma/paraganglioma (CP) is a rare neoplasm with most cases presented as single reports. Little is known about its pathogenesis and relationship with ordinary pheochromocytoma (PCC) or paraganglioma (PGL). Our study is aimed at analyzing the status of SDH and ATRX and identifying novel genetic changes in CP. Methods: 18 CP cases were collected. SDH and ATRX status was screened by immunohistochemistry. Targeted region sequencing (TRS) was successfully performed on formalin-fixed paraffin-embedded tissues in 2 cases within 3 years. Based on the TRS result, Sanger sequencing of BRAF and HRAS was performed in 15 cases (including the 2 cases with TRS performed), with 3 cases excluded due to the limited amount of tissue. Results: Histopathologically, all the cases were composite PCC/PGL-ganglioneuroma (GN). The GN components were either closely admixed or juxtaposed with the PCC/PGL component, with highly variable percentage (10-80%). All cases stained positive for SDHB and ATRX. HRAS and BRAF mutations were identified during TRS. In the subsequent Sanger sequencing, 20.0% (3/15) harbored BRAF mutations (K601E and K601N) and 46.7% (7/15) harbored HRAS mutations (Q61R, Q61L, G13R). The mutation rates were both significantly higher than reported in ordinary PCC/PGL. Conclusions: We demonstrated that composite PCC/PGL-GN might be a unique entity with frequent HRAS and BRAF mutations rather than genetic changes of SDH and ATRX. Our findings revealed the possible pathogenesis of composite PCC/PGL-GN and provided clues for potential treatment targets.

Composite Pheochromocytoma With Ganglioneuroblastoma: A Case Report

Introduction: A composite pheochromocytoma (PC) is an adrenal tumor that is often diagnosed post-operatively on histopathology. PCs are unique in that it is a combination of typicalpheochromocytoma and neural crest derived tumors. The incidence is reported to be less than 3%of adrenal neoplasms. The most common co-existing tumor within a PC is a ganglioneuroma. Wepresent a rare case of PC containing ganglioneuroblastoma (PC-GNBL) in a woman withoutsignificant biochemical manifestation of excess catecholamine production. Case Report: A 63-year-old woman with a prolonged history of uncontrolled hypertension on 4 oral anti-hypertensive medications (Amilodipine 10mg daily, Valsartan/HCTZ 320/25mg daily andClonidine 0.1mg/24h patch) and uncontrolled type 2 diabetes on insulin was diagnosed with a1.5x1.8x1.5cm right adrenal incidentaloma 2 years prior on CT imaging for abdominal pain. Hormonal evaluation was notable for plasma free metanephrine of 66 (<57pg/ml),normetanephrine 229 (<148pg/ml), and total metanephrines of 295 (205 pg/ml). However, 24-hour urine metanephrine evaluation was normal on two occasions: metanephrine 121 and 168mcg/24h (90-315), norepinephrine 237 and 336 mcg/24h (122-676) and total metanephrines 358and 504mcg/24 h (224-832). Hyperaldosteronism and hypercortisolism were ruled out. Follow-up CT scan 14 months later demonstrated growth of the right adrenal nodule to 1.7x2x2cm with49% washout. She underwent laparoscopic right adrenalectomy without perioperativecomplications. Pathology was consistent with a PC-GNBL. The PASS score was 7, consistentwith malignant pheochromocytoma. Within weeks of surgery, she had marked clinicalimprovement. Blood pressure was controlled on one anti-hypertensive and Hgb A1c decreased to7.1% from 11% without requiring insulin. CT abdomen/pelvis 6 months post-operatively did notshow evidence of metastasis. She was referred for genetic testing. Conclusion: This case highlights an unusual presentations of pheochmocytoma. It’s important to recognizethat resistant hypertension can present without episodic headaches, diaphoresis, palpitations, andwithout biochemical evidence of catecholamine excess. Composite PCs are indistinguishableclinically or radiologically from ordinary pheochmocytomas. These exceedingly rare mixedtumors are only diagnosed via surgical pathology. To date, there are only a few cases reported inthe medical literature of co-existing PC-GNBL tumors. Due to the scarcity of composite PCscases, important information regarding its presentation and prognosis are unknown. It remains tobe seen whether the GNBL part of the tumor changes the prognosis of the tumor. However, inour case, the clinical status of our patient improved.