see: Case example with operative note ganglioneuroma of sympathetic chain

Note: last updated before 2019

pNTs are members of tumors derived from the neural crest cells.

The neural crest cells are highly migratory and multipotent population that develop into many cell types and tissues throughout the body.

Tumors arising from the neural crest cells are extremely diverse; the nomenclature is confusing.

In general, tumors arising from the neural crest cells can be divided into 4 lineages: tumors of the sympathetic-adrenal lineage, tumors of the Schwann cell lineage, tumors of the melanocytic lineage (malignant melanoma), and multiple lineage tumor syndromes (MEN). pNTs are members of tumors derived from the neural crest cells.  

Neural Crest Cell Tumors (PNT's = peripheral neuroblastic tumors) (adapted from Maguire 2015)

Comparison between sympathetic trunk ganglioneuroma and vagal paraganglioma:

Tumors of the sympathetic-adrenal lineage include pNTs, pheochromocytoma (PCC) and paraganglioma (PGL). Both PCC and PGLs are rare, vascularized neuroendocrine tumors that arise from paraganglia. Paraganglia are clusters of neuroendocrine cells dispersed throughout the body. The largest collection is in the adrenal medulla which gives rise to pheochromocytomas. The extraadrenal paraganglia include the paraverteral paraganglia (organs of Zuckerkandl), those associated with aorticopulmonary chain (the jugulotympanic ganglia, ganglion nodosum of the vagus, carotid bodies, and aortic bodies), and clusters located in the oral cavity, nose, nasopharynx, larynx, and orbit. The paravertebral paraganglia usually have sympathetic connection and contain chromaffin cells (pheochromocyte). As such, tumors arising from the paravertebral paraganglia are essentially "extra-adrenal pheochromocytoma" and frequently secret excess catecholamine. The major difference between them is that paravertebral paragangliomas secret norepinephrine whereas "intra-adrenal pheochromocytomas" secret epinephrine. This is because the enzyme that converts norepinephrine to epinephrine (phenylethanolamine N-methyltransferase, PNMT) requires cortisol as a cofactor which exists in the adrenal medulla. Tumors arising from the paravertebral paraganglia are usually located outside of the HN area (chest, abdomen, and bladder). The paragangliomas in the HN area are frequently parasympathetic, comprised of chromaffin-negative cells. As such, paragangliomas in the HN area usually do not secret catecholamines. Morphologically, PGLs are highly vascularized, thin-encapsulated masses composed of clusters of chief cells in a highly vascular stroma with silver enhancement (Zellballen). PGLs can become malignant. However, there are no histologic criteria to differentiate benign from malignant paragangliomas because even benign paragangliomas exhibit cellular mitoses, nuclear pleomorphism, and capsular invasion. Malignant PGLs should be diagnosed if there is biopsy-proven metastasis to the regional LNs, lungs or bones. In general, there are about 4% of PGLs in the HN area are malignant (16% in Vagal PGL; 2-6% in Carotid body tumors and jugulotympanic PGLs).

Tumors of the Schwann cell lineage include both benign nerve sheath tumors (NSTs) and malignant peripheral nerve sheath tumors (MPNSTs). Benign NSTs primarily include neurofibroma and schwannoma. Although they both arise from Schwann cell lineage, they are pathologically and genetically different.  Schwannomas are well-circumscribed, encapsulated masses that are attached to the nerve or splay the nerve fibers which are usually incorporated into the capsule. Histologically, schwannomas are entirely made up of benign neoplastic Schwann cells, presented as two growth patterns: Antoni A, which exhibits high density of neoplastic Schwann cells arranged in fascicles with little stromal matrix, and Antoni B, which exhibits low cellularity along with microcysts and myxoid changes. In contrast, neurofibromas are unencapsulated masses comprised of a mixture of neoplastic Schwann cells, perineurial-like cells and fibroblasts. The fibers of involved nerve are usually intermixed with tumor components, making it impossible to separate the lesion from the nerve. The vast majority of both schwannomas and neurofibromasoccur sporadically and singly. Multiple schwannomas are associated with NF 2 whereas multipleneurofibromas are associated with NF1. MPNSTs can arise from pre-existing neurofibroma. In patients with NF1, the risk of developing an MPNST is about 8-13%. Malignant transformation of schwannomas is extremely rare. Such change is only reported in patients with melanotic schwannomas. 

Recently, perineuromas are categorized as another form of benign NSTs. However, these tumors are comprised of perineural cells, which is not derived from neural crest cells but local mesenchymal cells. They are negative for S100 but positive for EMA (epithelial membrane antigen and claudin-1 (a membrane proteins of the tight junction). Similar to the case in neurofibromas, the nerve fibers in perineuroma also course through the tumor. 

MEN is an autosome dominant inherited endocrine cancer syndrome subcategorized as MEN 1, MEN 2A and 2B based on overlapping clinical phenotypes. MEN 2A/B but not MEN 1 is associated with neural crest cell-derived tumors. For instance, MEN 2A is associated with medullary thyroid cancer arising from parafollicular C cells and pheochromocytoma arising from pheochromocytes (chromaffin cells)of the adrenal medulla. MEN 2B is associated with diffuse gastrointestinal ganglioneuromatosis. The mechanism behind is due to the mutation of RET which is required for the migration of neural crest cells into foregut and the subsequent colonization and differentiation. While MEN2B frequently presents with diffuse gastrointestinal ganglioneuromatosis, mutation of RETin sporadic pNTs remains controversial. Several gene mutations have been thought to be associated with the development of pNTs. For instance, studies have shown that PHOX2B mutation is associated with both familial and sporadic NB. Amplification of MYCN, a gene encoding a Myc family transcription factor, is found in a quarter of sporadic NB and associated with worse prognosis. 

GNs are non-vascularized tumors. As such, GNs appear to be hypodense masses without significant enhancement (Figure 1). On MRI scan, our case exhibited an isodense T1, hyperdense on T2, avidly enhanced tumor (Figure 2), lacking the“salt and pepper” appearance which is commonly seen in pateints with PGLs (Links in Iowa Protocols).  

Ganglioneuroma (GN) are rare and slow-growing tumors that arise from sympathetic ganglion cells. They belong to the family of peripheral neuroblastic tumors (pNTs) which include neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. GNs represent the final stage of maturation of pNTs thus are benign. Morphologically, GNs are encapsulated, non-vascular tumors comprised of large mature ganglion cells; whereas neuroblastomas are composed of small, primitive-appearing cells with dark nuclei scant cytoplasm and poorly defined cell borders growing in solid sheets.  

References

Maguire LH, Thomas AR, Goldstein AM. Tumors of the neural crest: Common themes in development and cancer.  Dev Dyn. 2015 Mar;244(3):311-22

Kumar V, Abbas, A, Fousto N. Robbins and Cotran Pathologic Basis of Disease. 7th Edition. 

Rankine AJ, Filion PR, Platten MA, Spagnolo DV. Perineurioma: a clinicopathological study of eight cases. Pathology. 2004 Aug;36(4):309-15.

Hornick JL, Fletcher CD. Soft tissue perineurioma: clinicopathologic analysis of 81 cases including those with atypical histologic features. Am J Surg Pathol. 2005 Jul;29(7):845-58.

Bunge MB, Wood PM, Tynan LB, Bates ML, Sanes JR. Perineurium originates from fibroblasts: Demonstration in vitro with a retroviral marker. Science 243: 229–231.