Malignant Pheochromocytoma  

Azzoug S. , Amirou Al. , Rabehi L. , Chentli F.
Department of Endocrine and Metabolic diseases, Bab El Oued Hospital, Algiers, Algeria
Author    Correspondence author
International Journal of Clinical Case Reports, 2015, Vol. 5, No. 21   doi: 10.5376/ijccr.2015.05.0021
Received: 14 Apr., 2015    Accepted: 28 May, 2015    Published: 09 Jun., 2015
© 2015 BioPublisher Publishing Platform
This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Preferred citation for this article:

Azzoug et al., 2015, Malignant Pheochromocytoma, International Journal of Clinical Case Reports, Vol.5, No.21 1-4 (doi: 10.5376/ijccr.2015.05.0021)


Pheochromocytoma is malignant in approximately 10%. Malignancy is evidenced by the presence of metastases outside chromaffin tissue sites. We report here the observations of four malignant pheochromocytoma (two male and two female) encountered in our practice during a period of twenty five years. They were aged between 6 and 33 years at first presentation. Two were sporadic and two were linked to hereditary syndromes, one multiple endocrine neoplasia type 2 (MEN2) and one neurofibromatosis type 1. The adrenal tumor measured between 24 and 115 mm, it was bilateral in the MEN2 syndrome and unilateral in the reminder cases. Metastases were present at first presentation in two cases, in the immediate post operative course in one case and many years after primary surgery in thepatient presenting MEN2 syndrome. Malignant pheochromocytoma is rare; the diagnosis of malignancy may be present at first diagnosis but sometimes it may occur many years after primary surgery therefore lifelong monitoring is mandatory.

Malignant pheochromocytoma; Chromaffine tissue; Hereditary syndromes; Lifelong monitoring

Malignant pheochromocytoma is a rare disease with a dire prognosis. Malignancy is ascertained by the presence of metastases in sites normally devoid of chromaffin tissue. The aim of this work is to report the clinical, diagnostic procedures and evolution of four malignant pheochromocytoma cases encountered in our practice during a period of twenty five years.

Table 1.

Table 1 Characteristics of patients with Malignant pheochromocytoma

A female patient, 23 years old, with a family history of neurofibromatosis in her father and two brothers was sent for exploration of a right adrenal mass discovered at abdominal ultrasound performed for abdominal pain. Clinically, she presented typical cutaneous signs of type 1 neurofibromatosis (café au lait spots, freckling, neurofibromas). However, there was no hypertension nor adrenergic signs. Abdominal computed tomography showed a huge heterogeneous right adrenal mass measuring 50 mm, moderately enhanced after injection (Figure 1). Further exploration with I131-MIBG scintigraphy showed an uptake of the right adrenal mass without other locations. Urinary metanephrines were normal. The patient was operated on by laparoscopy. There was a rounded fibrous mass of 7 cm diameter, bleeding at the slightest contact.

Figure 1 Abdominal CT showing huge right adrenal mass

Histopathological study concluded to a pheochromocytoma with an aggressive potential. PASS score (Pheochromocytoma Adrenal Gland of the Scaled Score) wasgreater than 4. Postoperative evolution was devastating with occurrence after three months of multiple secondary locations (liver, muscle, peritoneal, parietal, lung and bone marrow) shown at CT scan (Figures 2, 3), I131-MIBG scintigraphy (Figure 4) and bone scintigraphy (Figure 5). The patient received chemotherapy and I131-MIBG metabolic radiotherapy.

Figure 2 Abdominal CT : hepatic metastases

Figure 3 Pulmonary CT: Lung metastases

Figure 4 Metastases uptake at I-MIBG scintigraphy

Figure 5 Metastases uptake at bone scintigraphy

Observation 2
A female patient aged 27, in whom the diagnosis of multiple endocrine neoplasia type 2 [NEM2], combining a bilateral pheochromocytoma and medullary thyroid carcinoma was made at the age of six years. She underwent bilateral adrenalectomy and total thyroidectomy. Histopathological study concluded to bilateral pheochromocytoma and hyperplasia of C cells. She was in remission since.
Twenty years later, adrenergic signs recurred. Biologically, metanephrines increased again. Abdominal computed tomography showed four abdominal lymph nodes, they were heterogeneous with areas of necrosis and highly vascularized on contrast enhanced CT. These lymph nodes were visualized at MIBG scintigraphy. The diagnosis of malignant pheochromocytoma was therefore made. She received chemotherapy and died eighteen months after diagnosis of malignancy.
Observation 3
A male patient, 26 years old, was admitted for severe hypertension lasting for three years associated with adrenergic sings and orthostatic hypotension. Biologically, there was a rise of Metanephrines. On computed tomography there was a right side adrenal mass of 7 cm. The patient was operated on. Histopathological study concluded to a 8 cm pheochromocytoma with vascular invasion but not capsular involvement. Postoperative evaluation [CT scan] showed a residual tumor of 22x31 mm uptaking at MIBG scintigraphy. Surgical resection of the process could not be performed due to locoregional invasion found during surgical procedure.
Observation 4
A 33 years old male patient, in whom a large left adrenal mass of 125 mm with central necrosis associated with a metastatic liver mass of 90 mm was discovered at abdominal ultrasound performed on the occasion of pain in the right hypochondria. Clinically there was deterioration of general condition, adrenergic signs and resistant hypertension. Urinary metanephrines were very high. MIBG scintigraphy showed an heterogeneous hepatic uptake but not adrenal uptake. Diagnosis of malignant pheochromocytoma was therefore made.
The four cases of malignant pheochromocytoma represent 10% of all pheochromocytomas encountered in our department (41 cases) which corresponds to literature data (Ajalle, 2009). Hypertension is the most frequently presenting symptom (90%) (Baguet, 2004). It was found in three of our four cases. Atypical signs such as abdominal and back pain occurred more frequently in malignant pheochromocytomas. It was the presenting sign in two of our patients. Tumors were large (higher than 5 cm) in three patients, this criterion is in favor of a greater risk of malignancy (Lenders, 2005). Malignant pheochromocytoma can be sporadic or part of a familial syndrome such as multiple endocrine neoplasia type 2 (MEN 2), type 1 neurofibromatosis (NF1), von Hippel-Lindau-(VHL) disease and mutations of nuclear succinate dehydrogenase gene (SDH). Syndromic pheocromocytoma was found in two of our patients. The first presents NF1. Pheochromocytoma is rare in this condition present in 1% among which 12% are malignant. The second patient presented a NEM 2A. Malignant form in this condition is rare (less than 5%) (Fishbein, 2013; Jafri and Maher, 2012). For the fourth case reported in 1993 we could not exclude SDH mutations as these mutations were discovered in 2000 (Baysal, 2002).
Time for occurrence of metastases is variable, as they were already present at diagnosis in two of our cases, and occurred after 20 years in one case.
Surgery is the mainstay treatment, open surgery is recommended for large, invasive or likely to be malignant pheochromocytoma to ensure complete tumor resection and prevent tumor rupture (Lenders, 2014), tumor rupture and seeding may explain the postoperative evolution in our first patient. Even if surgery is not always curative it may be considered as a debulking measure as anti-cancer therapies (chemotherapy, I131 MIBG metabolic radiotherapy, targeted therapy), are not very effective. They can improve the wellbeing and ensure a partial remission (Scholz, 2007). Conventional chemotherapy can also be used. It is based on the combination of cyclophosphamide, vincristine and dacarbazine (CVD) (Huang, 2008). The first patient received I131-MIBG metabolic radiotherapy and conventional chemotherapy with partial improvement. Recent years have seen the advent of new treatments such as of tyrosine kinase inhibitors, somatostatin analogs and alkylating agents (temozolomide). These drugs should be subjected to larger studies to prove their efficacy and safety.
Pheochromocytoma has an unpredictable course. There is not a benign pheochromocytoma, but pheochromocytoma with “non-aggressive potential”, hence the need for lifelong monitoring of any pheochromocytoma with annual measurements of plasma free metanephrines or urinary fractionated metanephrines. Genetic counseling is necessary, given the relative frequency of familial forms.
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