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Laparoscopically Resected Composite Pheochromocytoma- Ganglioneuroma

Na Rae Kim, Taeeun Kim1, Jeong Nam Lee2, Young Sil Eom3, Dong Hae Chung, Sanghui Park, Hyun Yee Cho Department of Pathology, Gachon University Gil Hospital, Incheon; Department of Pathology1, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; Department of Surgery2, Division of Endocrinology and Metabolism, Department of Internal Medicine3, Gachon University Gil Hospital, Incheon, Korea


INTRODUCTION
Mixed adrenal tumors composed of more than one cell type are uncommon; they are called composite pheochromocytomas [1] and corticomedullary mixed tumors [2]. This type of pheochromocytoma is called composite or mixed, depending on whether pheochromocytoma and nonpheochromocytomatous combined components are of the same or different embryonic origin. About 50 cases of composite pheochromocytoma have been published in the English medical literature [3]. Composite pheochromocytoma is a well-defined neoplasm of the medulla and the tumor consists of both endocrine and neural components. Histologically, the endocrine portion is that of a pheochromocytoma, whereas the neural portion has been reported as ganglioneuroma, ganglioneuroblastoma, neuroblastoma, neuroendocrine carcinoma or malignant pe-ripheral nerve sheath tumor [4]. Pheochromocytoma is usually characterized by a catecholaminergic effect with hypertension, whereas ganglioneuroma is a rare mature neuroblastic tumor that is typically nonmetabolically active, and so it is usually asymptomatic [5,6].
To date, less than 50 cases of composite pheochromocytoma have been reported [1][2][3][4][5][6], and two Korean cases of composite pheochromocytomas have been reported in the English and Korean literature [5,6]. Here, we report additional six cases of unusual tumor of the adrenal gland and the tumor exhibited a mixed phenotype composed of cells of adrenal medullary and neural lineages.

Clinical summary
Case 1 was a 54-year-old normotensive woman visited an endo-crinology clinic of Gachon University Gil Hospital in February 2010.
She previously had visited the hospital in May 2000 to evaluate incidentally found right adrenal mass. Abdominal computed tomography (CT) showed a 4 cm-sized well defined heterogeneous attenuated soft tissue mass in right adrenal gland (Fig. 1A). She did not complain any subjective symptoms and wanted to be regular followup. During 10 years of preoperative follow-up period, she experienced two episodes of headache. Case 2 was a previously healthy 33-year-old man came to Gachon University Gil Hospital in order to evaluate incidentally found adrenal mass at health screening examination. Pre contrast CT revealed an 11 cm-sized right adrenal mass with heterogenous low density, which was compressing liver At that time, he also undertook a brain magnetic resonance for his severe headache. Abdominal CT taken at the emergency room showed a well-defined 5.0 cm-sized heterogeneous mass at the right adrenal gland (Fig. 1C). Case 4 was a 58-year-old man who The biochemical profiles showed that the level of preoperative urine metanephrine was increased in all the 6 cases and the urine VMA level was elevated in cases 2, 3, and 6. But, endocrine profile of blood and/or urine showed increased catecholamines including epinephrine, norepinephrine or dopamine. To control the preoperative hypertension, calcium channel blockers, including bevantolol and nifedipine and alpha-antagonists were administered. All the cases underwent laparoscopic adrenalectomies. During the followup period ranging from 3 months to 6 years, their hypertension was controlled without any medication after adrenalectomy. The levels of blood/urine catecholamines returned to normal with no radiologic evidence of metastasis after the operation. The pre-and postoperative the 24 hour analysis of urine VMA and metanephrine were shown in Table 1. All the patients and their families were not associated with neurofibromatosis or multiple endocrine neoplasm (MEN) syndrome.

Pathological findings
Grossly, the laparoscopically resected specimens consisted of irregular pieces of firm pinkish tan tissue in cases 2, 3, and 6. A well defined encapsulated oval shaped brownish yellow mass was found in cases 1, 4, and 5. The size of each tumor ranged from 3.0 to 11.0 cm. The cut surface was yellowish brown to mahogany-brown color ( Fig. 1E, F). The specimen was received in 10% neutral-buffered formalin and processed routinely. In addition to routine hematoxylin and eosin stains, immunohistochemistry for phosphorylated neu- That portion was diagnosed as pheochromocytoma. The bundles of spindle cells were admixed with the ganglioid cells, and the findings were consistent with ganglioneuroma (Fig. 2C). The ganglioid cells were strongly positive for phosphorylated neurofilament (Fig.   2D) and S-100 protein, while the large chromaffin cells were positive for synaptophysin (Fig. 2E) and chromogranin A with admixed S-100 protein-positive sustentacular cells (Fig. 2F). The tumors were diagnosed as composite pheochromocytomaganglioneuromas. The proportions of ganglioneuroma in cases 1, 2, 3, 4, 5, and 6 comprised from 30%, 40%, 10%, 30%, 50%, and 60%, respectively. http://www.enm-kes.org Composite pheochromocytoma-ganglioneuromas are composed of chromaffin cells and the sympathetic ganglion cells [1][2][3][4][5][6]. The histogenesis of composite adrenal medullary tumors has been attributed to the common embryologic origin of the chromaffin and neuronal cells from the neural crest. To date, less than 50 cases of composite pheochromocytoma-ganglioneuromas have been reported since the first description [8]. The composite tumor has been used to describe tumors that theoretically arise from a common embryologic progenitor, whereas mixed pheochromocytomas designate tumors that have no common embryologic ancestry.
In about 70% of composite adrenal medullary tumors, the accompanying second tumor component was ganglioneuroma. The clinical symptoms associated with composite pheochromocytoma-ganglioneuroma are usually similar to those of ordinary pheochromocytoma, but secretion of vasoactive intestinal polypeptides (VIP) is more common with composite pheochromocytoma-ganglioneuroma compared to the latter [3]. Hypertension and its related symptoms are common in composite pheochromocytoma-ganglioneu-roma. Occasional normotensive patients with composite tumors may be explained by the theory of autonomic regulation by ganglioneuroma, and it partially depends on the complex biochemical interaction and proportion of each element [9]. Rarely, watery diarrhea, hypokalemia and achlorhydria syndrome due to a functional VIPsecreting tumor can be observed in patients with composite pheochromocytoma-ganglioneuroma, and vasodilatory action of VIP also contributes the normotension [10]. Commonly observed muscle weakness may be related to associated hypokalemia [11]. Adrenal composite tumor may be incidentally discovered, masquerading as acute relapsing pancreatitis [5]. These composite tumors of the adrenal medulla may be associated with sporadic tumors or as part of neurofibromatosis type I, von Hippel-Lindau disease, MEN 2A and MEN 2B syndromes [12]. The present cases were shown to have no relation to neurofibromatosis, but 6% to 11% of composite pheochromocytomas are associated with genetic conditions. In general, the patients with pheochromocytoma are likely to develop papillary carcinoma, which may be related to the undulatory release of thyroid hormone secondary to circulating catecholamines [6,13].
Albeit rare, these findings should warn the patients to undergo regular examination of the thyroid gland.
Both pheochromocytoma and ganglioneuroma commonly manifests radiologically as a well-defined, smooth or lobulated mass with or without calcification. CT is accurate in the detection of pheochromocytomas. However, nearly one third of all cases show a nonspecific appearance that may overlap with the appearance of adrenocortical carcinoma [14]. In the same manner, composite pheochromocytoma and ganglioneuroma shows heterogenous radiologic, gross and microscopic features with varying admixtures of ganglioneuroma and pheochromocytoma components [15].
The clinical significance of microscopically detecting the other component from pheochromocytoma has not yet been clarified and absence of N-myc amplification [15][16][17]. A review by Lam and Lo [15] suggests that the composite tumors are seen in older patients and are bigger than typical pheochromocytomas, which is possible that they are more aggressive than pheochromocytoma alone [10].
Here, all the six cases of composite pheochromocytoma-ganglioneuroma undertook laparoscopic adrenalectomies. Laparoscopic adrenalectomy provides the benefits of a minimally invasive approach, and is regarded to be the surgery of choice for pheochromocytoma, compared to open resection, due to the improved preoperative hemodynamic stability and the lessened need for postoperative analgesics [18].

SUMMARY
In summary, microscopic identification of a non-pheochromocytomatous component from pheochromocytoma is important because cumulative cases of composite pheochromocytoma-ganglioneuroma may be used to predict the biologic behavior of this rare tumor.