Adrenal ganglioneuroma: What you need to know.

Adrenal ganglioneuromas (GNs) constitute rare, differentiated tumors which originate from neural crest cells. GNs are usually hormonally silent and tend to be discovered incidentally on imaging tests. Adrenalectomy is the gold standard for the treatment of primary adrenal GNs. Nevertheless, preoperative differential diagnosis of GNs remains extremely challenging, and thus histopathological examination is required in order to confirm the diagnosis of GN. Overall, prognosis after surgical resection seems to be excellent, without any recurrences or need for adjuvant therapy.

Core tip: Adrenal ganglioneuromas (GNs) are uncommon, differentiated tumors which originate from neural crest cells. These lesions are usually discovered incidentally because they tend to be hormonally silent. Even though, surgery is the gold standard for the treatment of adrenal GNs, the process of preoperative differential diagnosis remains extremely challenging. Therefore, histologic examination is necessary in order to confirm this rare diagnosis. In general, there is no need for adjuvant treatment and the overall prognosis of these patients is excellent.

INTRODUCTION

Ganglioneuromas (GNs) constitute rare, differentiated tumors which originate from neural crest cells[1]. As such, they are usually located in the retroperitoneal space (32%-52%) or in the posterior mediastinum (39%-43%). Less commonly, GNs can be seen in the cervical region (8%-9%) as well[2,3]. Interestingly enough, thoracic tumors have been found to be larger than non-thoracic ones at the time of diagnosis[4]. Adrenal GNs occur most frequently in the fourth and fifth decades of life, whereas GNs of the retroperitoneum and posterior mediastinum are usually encountered in children and younger adults. GNs seem to develop in females and males with equal rates; yet most of our data derive from case reports or small case series[5-7]. Nonetheless, a familial predisposition as well as an association with Turner syndrome and multiple endocrine neoplasia II have also been suggested[5].

Commonly, adrenal GNs are hormonally silent and as a result can be asymptomatic; even when the lesion is of substantial size[5,8]. On the other hand, it has been reported that up to 30% of patients with GNs may have elevated plasma and urinary catecholamine levels, but without exhibiting any symptoms of catecholamine excess[4]. Additionally, it has been noted that ganglion cells can secrete vasoactive intestinal peptide (VIP), whilst pluripotent precursor cells sometimes produce steroid hormones, such as cortisol and testosterone[9,10].

IMAGING

Adrenal GNs are usually discovered incidentally due to the widespread use of computed tomography (Figure 1) and MRI (Figure 2) imaging techniques[2,11]. Particularly, GNs account for approximately 0.3%-2% of all adrenal incidentalomas[12-14]. In most cases, ultrasonography reveals a well-circumscribed, homogenous, hypo-echogenic lesion[15]. Furthermore, CT findings are usually compatible with a well-defined, lobular-shaped, solid, encapsulated mass. These tumors can been seen ranging from iso-attenuating to hypo-attenuating lesions compared to muscle signals[15]. Usually, the mass surrounds major blood vessels without imposing compression or occlusion[16]. Fine, punctate calcifications are found at a frequency ranging from 20% to 69% and are considered highly indicative of GNs[5,11]. On magnetic resonance imaging, T1-weighted images tend to have homogeneously low or intermediate signal, whereas T2-weighted images have heterogeneously intermediate or high signal[17]. Arguably, the latter is caused by the presence of the myxoid matrix along with a relatively low number of ganglion cells[18]. Furthermore, gadolinium administration can result in delayed and progressive enhancement of the lesion[8,15].

Figure 1

Axial computed tomography of left adrenal ganglioneuroma: Well-defined, solid, encapsulated mass (in intravenous contrast). A: Non-enhanced image; B: Enhanced image (venous phase).

Figure 2

Coronal magnetic resonance imaging of left adrenal ganglioneuroma: A coronal T1-weighted out-of-phase image shows intracellular lipid and no signal loss within the lesion.

In reality, the aforementioned radiology findings are not pathognomonic of adrenal GNs[15]. Particularly the preoperative misdiagnosis rate of adrenal GNs based on CT and MRI findings has been attested to be 64.7%[5]. Also, MIBG (131-metaiodobenzylguanidine) scintigraphy produces similar results in GNs, ganglioneuroblastomas and neuroblastomas[2,15]. Recently, PET scans have been proclaimed to facilitate the diagnostic process. Particularly, Standardized Uptake Value (SUV) of 3.0 or higher has been suggested to distinguish malignant from benign adrenal lesions with 100% sensitivity and 98% specificity[19]. However, Adas et al[20] did report an adrenal GN with a SUV of 4.1 that was determined to be histologically benign. Taking everything into consideration, preoperative differential diagnosis of GNs remains extremely challenging and includes a variety of lesions, such as ganglioneuroblastoma, neuroblastoma, composite pheochromocytoma, adrenal cortical adenoma and adrenocortical carcinoma[2,21].

HISTOPATHOLOGIC FEATURES

Ultimately, histopathological examination is required in order to confirm the diagnosis of GN (Figure 3). In the vast majority of cases, GNs are histologically benign lesions GNs which can be classified into two main categories[4]. Firstly, “mature type” GNs comprise of mature Schwann cells, ganglion cells and perineural cells within a fibrous stroma whilst completely lacking neuroblasts and mitotic figures[8]. Secondly, “maturing type” GNs consist of similar cellular populations with miscellaneous maturation degrees, ranging from fully mature cells to neuroblasts. Nevertheless, detection of neuroblasts is typically indicative of neuroblastomas or ganglioneuroblastomas. These types of neurogenic tumors have the potential to evolve into GNs[15]. Characteristically, GNs exhibit immunohistochemical reactivity for specific markers such as S-100, vimentin, synaptophysin and neuron-specific enolase[17].

Figure 3

Histopathologic features of adrenal ganglioneuromas. A: Margin between adrenocortical parenchyma and adrenal ganglioneuroma with Schwann cells in adipose stroma (H and E × 100); B: Schwann cells in adipose stroma (H and E × 400); C: Schwann and ganglion cells in non-adipose stroma (H and E × 200); D: Schwann cells and multiple ganglion cells (H and E × 200); E: Protein S100 (+) Schwann cells (immunostaining × 400); F: Neuron-specific enolase (+) ganglion cells (immunostaining × 200). H and E: Hematoxylin and eosin.

GENETIC FEATURES

The tyrosine kinase receptor ERBB3 is one of the most commonly up-regulated genes in GNs[22]. Additionally, recent case series have found high expression of GATA3 in all of their GN tumors (100%) meaning that this may be a very reliable marker for GNs[23,24]. Lastly, the coexistence of GN with neuroblastoma has been associated with a hemizygous deletion of 11q14.1-23.3. Indeed, the predisposition to the development of neurogenic tumors may be attributed to the deletion of the NCAM1 and CADM1 genes which lie in 11q[25]. In contrast to neuroblastomas though, GNs do not seem to exhibit MYCN gene amplifications[4].

MANAGEMENT

Last but not least, literature is consistent with the fact that when dealing with large (> 6 cm) adrenal incidentalomas there is a 25% probability of the lesion being an adrenocortical carcinoma. Geoerger et al[4] described local lymph node involvement in two GN patients and one case of distant metastasis to soft tissues in their 49-patient case series. Nonetheless, malignant GNs remain extremely rare occurrences[21]. Ultimately, surgery constitutes the gold standard for the treatment of primary adrenal GNs[4,26]. Even though, laparoscopic adrenalectomy is usually the procedure of choice, a number of variables (e.g., hormonal activity, tumor location, and proximity to adjacent structures) also need to be taken into account when deciding on the best approach to operate on these rare tumors[24]. Of note, wide excisions are unnecessary since adrenal GNs rarely metastasize or recur. Postoperatively, there is no need for adjuvant therapy in patients with adrenal GNs and their prognosis is excellent[4,21].

CONCLUSION

Adrenal GNs are uncommon, differentiated tumors which originate from neural crest cells. These lesions are usually discovered incidentally and tend to be hormonally silent. Even though, adrenalectomy is the gold standard for the treatment of adrenal GNs, the process of preoperative differential diagnosis remains extremely challenging. Ultimately, histologic examination is necessary in order to confirm this rare diagnosis. Postoperatively, there is no need for adjuvant treatment and the overall prognosis of these patients is excellent.