Clinical Oncology: Case Reports

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Case Report, Clin Oncol Case Rep Vol: 5 Issue: 7

EDP Protocol For Metastatic Inoperable Pheochromocytoma: A Case Report

Shwartz L1, Gafter-Gvili A1, Buchrits S1, Goshen S1, Halperin E1*

1Department of Internal Medicine A, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel, 2 Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel

*Corresponding Author: Erez Halperin
Department of Internal Medicine A, Beilinson Campus, Rabin Medical centre, Israel
E-mail: [email protected]

Received: June 30, 2022; Manuscript No: COCR-22-68207;
Editor Assigned: July 02, 2022; PreQC Id: COCR-22-68207 (PQ);
Reviewed: July 17, 2022; QC No: COCR-22-68207 (Q);
Revised: July 19, 2022; Manuscript No: COCR-22- 68207 (R);
Published: July 28, 2022; DOI: 10.4172/cocr.5(7).240

Citation: Shwartz L, et al. (2022) EDP Protocol For Metastatic Inoperable Pheochromocytoma: A Case Report. Clin Oncol Case Rep 5:7


Introduction: Pheochromocytoma and Paraganglioma (PPGLs) are rare neuroendocrine tumors which are known for their excessive catecholamines secretion and their variable clinical presentation. The majority of PPGLs are benign. As such, therapeutic options for the treatment of metastatic pheochromocytoma are limited, especially when complete respectability is impossible. Moreover, the acceptable chemotherapy regimen doesn’t affect overall survival of these patients. We report a case of a patient with neurofibromatosis type 1 and inoperable metastatic pheochromocytoma, treated with a chemotherapy protocol derived from the treatment of adrenocortical carcinoma and the partial response seen to this treatment.   

Case presentation: 48-year-old caucasian woman with a history of neurofibromatosis type 1 presented with epigastric pain, dry mouth, and hypertension. Her blood work revealed elevated Aminotransferases levels (AST=53 U/L, ALT=91 U/L), Serum Alkaline Phosphatase (ALP) levels and Gamma-Glutamyl Transferase (GGT) levels (ALKP=188 U/L ,GGT=250 U/L) with high levels of lactate dehydrogenase (LDH= 797 U/L). An abdominal-pelvic ultrasonography demonstrated 8.9 cm X 8 cm X7 cm adrenal mass with possible liver metastases. Chest-abdomen-pelvis contrast enhanced Computed Tomography (CT) revealed space occupying lesion in the right adrenal, penetrating the inferior vena cava, and involving the right kidney, the left and right renal veins, and the aorta. Liver metastases were observed as well. Urine normetanephrine was 7173.5 mcg/24-hours, Normetanephrine/ creatinine ratio was 6676 and metanephrine/creatinine ratio was 225. A presumptive diagnosis of metastatic pheochromocytoma was made and subsequently validated in histopathology of a liver biopsy. Due to the proximity of the tumor to large vessels, debulking procedure couldn’t be performed.  She received 6 cycles of chemotherapy protocol used for the treatment of ACC- etoposide, doxorubicin, and cisplatin (EDP regimen). Follow-up urine normetanephrine decreased to 390 mcg/24-hour and the patient's symptoms relieved. In a 68Ga-DOTATATE positron emission tomographic scan, both the right adrenal mass and the diffused liver metastases had shrunk. However, the patient's death was determined only four months after the diagnosis, due to internal bleeding.

Conclusions: To the best of our knowledge, this is the first reported case of metastatic pheochromocytoma that showed a partial response to ACC chemotherapy regimen. This case raises the possibility that other chemotherapy regimens then CVD, merit further investigation in the setting of metastatic pheochromocytoma.

Keywords: Metastatic pheochromocytoma; CVD chemotherapy; EDP chemotherapy; Neurofibromatosis type 1; PPGL


Pheochromocytoma and Paraganglioma (PPGLs) are neuroendocrine tumours which are derived from either the sympathetic or parasympathetic nervous system and are known for their excessive catecholamine secretion [1,2]. Patients with neurofibromatosis type 1 are at an increased risk of developing malignancies that may be related to NF1 gene dysfunction and PPGLs occur in 1% to 3% of NF1 patients [3,4]. The majority of PPGLs are benign, while metastatic pheochromocytomas are rare. As such, the best treatment for metastatic pheochromocytoma is not well established. Treatment options include surgical resection, systemic chemotherapy, targeted radiopharmaceutical agents [e.g., 131I-MIBG or somatostatin analogues (90YDOTATATE and 177Lu-DOTATATE), radiation therapy and radiofrequency ablation when feasible surgical resection (tumour mass reduction) is the desired initial treatment even for debulking purposes [4]. The recommended regimen in patients with unresectable PPGLs is a combination chemotherapy with Cyclophosphamide, Vincristine, and Dacarbazine (CVD) [5]. This regimen may lead to disease stabilization or even partial response, performance status improvement, and symptom relief in up to 50% of patients [1,5]. However, this regimen is considered only palliative as it has not been shown to affect overall survival [6-8].

Herein, we present a case of a patient with neurofibromatosis type 1 (NF-1) and unresectable metastatic pheochromocytoma, treated with a chemotherapy protocol derived from the treatment of Adrenocortical Carcinoma (ACC) and the partial response seen to this treatment [9].

Case Report

A 48-year-old caucasian woman with a history of NF-1 presented to the emergency department with complaints of epigastric pain of 3 weeks duration. Her pain radiated to her back and became worse after eating and when lying down. Other complaints included a dry mouth. She denied any palpitations, headache, sweating, dizziness, or B symptoms.

Her vital signs were stable except for hypertension (Blood Pressure [BP]:150/95 mmHg). Her physical examination was remarkable for right upper quadrant tenderness, multiple neurofibromas and several café au lait macules. The complete blood count revealed leukocytosis with neutrophilia (WBCê??13.21 K/micl, NEUTê??10.5 K/micl) and normal haemoglobin and platelet count. Her liver function tests were significant for elevated aminotransferases levels (ASTê??53 U/L, ALTê??91 U/L), serum Alkaline Phosphatase (ALP) levels and Gamma- Glutamyl Transferase (GGT) levels (ALKPê??188 U/L, GGTê??250 U/L). Her total bilirubin and albumin levels were 0.53 mg/dl and 4.5 g/ dL respectively. High levels of Lactate Dehydrogenase (LDH) were observed (LDH=797 U/L). Additionally, her C-Reactive Protein (CRP) levels were slightly elevated (CRPê??1.35 mg/dl). The other Abdominal-pelvic Ultrasonography (US) was performed, demonstrating an 8.9 cm×8 cm×7 cm adrenal mass pushing the Inferior Vena Cava (IVC) forward with possible liver metastases. The main differential diagnosis of th e ad renal ma ss in th is pa ti ent included metastatic adrenocortical carcinoma and metastatic pheochromocytoma (due to her background). To further confirm the findings, chest-abdomen-pelvis contrast-enhanced Computed Tomography (CT) revealed Space Occupying Lesion (SOL) in the right adrenal: A heterogeneous tissue mass 8.9 cm×9.9 cm in size, penetrating the IVC, and involving the right kidney, the left and right renal veins and inseparable from the aorta (figure 1). Liver metastases have also been observed (figure 1).


Figure 1: Liver metastases of the left and right renal veins.

Full evaluation for hormonal secretion was performed, including 24-h urine for metanephrines and catecholamines excretion, which were increased. Urine normetanephrine was 7173.5 mcg/24 hours, Normetanephrine/ creatinine ratio was 6676 and metanephrine/ creatinine ratio was 225. The other endocrine screening tests were normal. A presumptive diagnosis of metastatic pheochromocytoma was made based on the imaging studies and the elevated metanephrines. This was subsequently validated in histopathology of a liver biopsy which demonstrated metastatic poorly differentiated tumour, compatible with an adrenal tumour, most probably pheochromocytoma. Immunohistochemistry was positive for chromogranin and synaptophysin. A high Ki-67 proliferation index (80%) was demonstrated as well. During the hospital course, she was started on alpha-blocker (Doxazosin) and beta-blocker (bisoprolol) for high blood pressure.

A multidisciplinary consultation was held to determine the best treatment strategy. Systemic chemotherapy was suggested as the only possible treatment since debulking procedure could not be performed due to the proximity of the tumour too large vessels. The choice of chemotherapy was debated with the conclusion that the standard CVD protocol for unresectable PPGLs would not suffice. As such, it was decided to adopt a protocol used for the treatment of ACC- Etoposide, Doxorubicin, and Cisplatin (EDP regimen). She received 6 cycles of combined chemotherapy. Follow-up urine normetanephrine, 2 months after admission decreased to 390 mcg/24 hours. The patient's abdominal bloating decreased, and her pain was relieved. After the fourth cycle, a 68Ga-DOTATATE PET/CT scan was carried out. Compared to the first CT scan, both the right adrenal mass and the diffused liver metastases had shrunk (figure 2).


Figure 2: CT scan of both the right adrenal mass and the diffused liver metastases.

Following this clinical, laboratory and radiologic improvement, additional therapeutic options were considered including somatostatin receptors and analogues, Peptide Receptor Radionuclide Therapy (PRRT) and personalized therapy based on Next Generation Sequencing (NGS).

A day after her sixth chemotherapy treatment, she was admitted with significant weakness and severe pain to our emergency department. She was hypotensive (Blood Pressure [BP]: 70/36 mmHg) and pale. Initial blood tests identified severe anaemia (Hemoglobin g/dL) and metabolic acidosis. Point-of-Care Ultrasound (POCUS) revealed blood in her left abdomen. After a discussion with the patient and her family and due to her poor prognosis, a palliative course of treatment was agreed on. She received supportive care which included blood transfusions, sodium bicarbonate and ringer lactate infusions. Three hours later, agonal breathings were observed with no recordable blood pressure or electrical cardiac activity. Life pronounced extinct.


We hereby described a case of an unusual presentation of metastatic pheochromocytoma. Our patient was diagnosed based on the clinical presentation, laboratory analysis, imaging, and pathologic findings.

The clinical presentation of pheochromocytoma is variable. The prominent symptoms, also have been known as the classic triad, are headaches, palpitations, and profuse sweating [10]. Clinically, patients with metastatic pheochromocytoma generally present similarly to patients with non-metastatic pheochromocytoma [11]. However, due to high tumour load, common manifestations include severe hypertension (sustained or episodic) and catecholamine-induced end-organ dysfunction (e.g ileus, organ ischemia and tachyarrhythmias) [11].

In this case, despite the high tumour burden, the patient's endocrine manifestations were relatively poor. Her only complaints were epigastric pain and dry mouth, and her blood pressure was only slightly elevated. Moreover, she responded well to the standard treatment (Combined α- and β-adrenergic blockade) although patients with metastatic pheochromocytoma may have difficulty treating symptomatic hypertension [1,4].

As for the treatment options, to the best of our knowledge, this is the first reported presentation of metastatic pheochromocytoma that showed a partial response to an ACC chemotherapy regimen. As mentioned above, the first-line therapeutic option for metastatic pheochromocytoma is surgical resection. When curative surgery is not performed, surgical debulking of the tumour is a clinically beneficial treatment option as reduction of tumour size palliates symptoms related to catecholamine secretion [6]. For patients with inoperable tumours, as in the present case, the combination of Cyclophosphamide, Vincristine and Dacarbazine (CVD) is the most common and potent chemotherapy regimen. Nevertheless, responses are usually short-lived, and this regimen is valuable mainly for patients with the symptomatic disease [1].

Due to her aggressive disease, she received a combination of etoposide, doxorubicin, and cisplatin (EDP regimen) instead of CVD chemotherapy. Mitotane plus EDP regimen represents the best approach to treatment in patients with advanced adrenocortical carcinoma, as rates of response and progression-free survival are significantly better with this regimen (23.2% vs. 9.2%, and 5.0 months vs. 2.1 months respectively) [9]. Yet, this regimen is not associated with improved overall survival [9]. After the intervention of the EDP combination regimen, a remarkable improvement in clinical, radiological, and biochemical markers (urine normetanephrine) was found.

Currently, there are several chemotherapy regimens other than CVD, for metastatic pheochromocytoma which has been evaluated in a small number of patients with various response rates. Srimuninnimit et al reported a patient diagnosed with metastatic pheochromocytoma and treated with cisplatin and 5-fluorouracil that showed an objective response after 3 cycles of chemotherapy [12]. Jirari et al reported a rare case of metastatic primary cardiac pheochromocytoma treated by adjuvant cytotoxic chemotherapy after surgical resection, with 5-year survival. The combination chemotherapy included vepecide plus carboplatyl and vincristine plus cyclophosphamide plus adriamycin [13].


Our case emphasizes the fact that a high index of suspicion is needed in order to diagnose pheochromocytoma, even when clinical symptoms are mild. Moreover, to our knowledge, our case is the first reported presentation of metastatic pheochromocytoma that showed a partial response to the ACC chemotherapy regimen. However, despite this significant response, the patient's death was determined only 4 months after the diagnosis, due to internal bleeding.

It is hard to draw conclusions from one case, but it raises the possibility that other chemotherapy regimens merit further investigation in the setting of metastatic pheochromocytoma.

This case report emphasizes the importance of finding an effective and validated chemotherapeutic regimen for inoperable metastatic pheochromocytoma.


  1. Plouin PF, Fitzgerald P, Rich T, Ayala-Ramirez M, Perrier ND (2012) Metastatic pheochromocytoma and paraganglioma: Focus on therapeutics. Hormone Metabolic Res 44: 390-399.
    [Google Scholar] [Cross Ref]
  2. Gruber LM, Erickson D, Babovicâ?Vuksanovic D, Thompson GB, Young Jr WF  (2017) Pheochromocytoma and paraganglioma in patients with neurofibromatosis type 1. Clinical Endocrinol 86: 141-149.  [Google Scholar] [Cross Ref]
  3. Rasmussen SA, Yang Q, Friedman JM (2001) Mortality in neurofibromatosis 1: An analysis using US death certificates. Am J Human Genetics 68: 1110-1118. [Google Scholar] [Cross Ref]
  4. Neumann HP, Young Jr WF, Eng C (2019) Pheochromocytoma and paraganglioma. New England J Med 381: 552-565.  [Google Scholar] [Cross Ref]
  5. Waguespack SG, Rich T, Grubbs E, Ying AK, Perrier ND (2010) A current review of the aetiology, diagnosis, and treatment of pediatric pheochromocytoma and paraganglioma. J Clinical Endocrinol  Metab 95: 2023-2037. [Google Scholar] [Cross Ref]
  6. Pacak K, Eisenhofer G, Ahlman H, Bornstein SR, Gimenez-Roqueplo AP (2007) Pheochromocytoma: Recommendations for clinical practice from the First International Symposium. Nat Clin Pract Endocrinol Metabolism 3: 92-102.  [Google Scholar] [Cross Ref]
  7. Nomura K, Kimura H, Shimizu S, Kodama H, Okamoto T (2009) Survival of patients with metastatic malignant pheochromocytoma and efficacy of combined cyclophosphamide, vincristine, and dacarbazine chemotherapy. J Clin Endocrinol  Metabol  94: 2850-2856. [Google Scholar] [Cross Ref]
  8. Huang H, Abraham J, Hung E, Averbuch S, Merino M (2008) Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: Recommendation from a 22�year follow�up of 18 patients. Cancer 113: 2020-2028.
    [Google Scholar] [Cross Ref]
  9. Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H (2012) Combination chemotherapy in advanced adrenocortical carcinoma. New Eng J Med 366: 2189-2197.  [Google Scholar] [Cross Ref]
  10. Lenders JW, Kerstens MN, Laurence AM, Prejbisz A, Robledo M, et al. (2020) Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: A position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension. J Hyperten 38: 1443. [Google Scholar] [Cross Ref]
  11. Publique A, Group EC, Cancer H, Program G (2020) National S. HHS Public Access. 38: 1443-1456.
  12. Srimuninnimit V, Wampler GL (1991) Case report of metastatic familial pheochromocytoma treated with cisplatin and 5-fluorouracil. Cancer Chemoth Pharmacol 28: 217-219.
    [Google Scholar] [Cross Ref]
  13. Jirari A, Charpentier A, Popescu S, Boidin P, Eisenmann B (1999) A malignant primary cardiac pheochromocytoma. Ann Thora Surg 68: 565-566.
    [Google Scholar] [Cross Ref]

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