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		Free Neuropathology 1:2 (2020)

		
	
		Opinion Piece

		
	
		The “neuroepithelial tumor”: Exchanging our trash can for an industrial size dumpster?

		
	
		
		Arie Perry

		
	
		
		Division of Neuropathology, Department of Pathology, University of California, San Francisco, USA

		
	
		Corresponding author:

		Arie Perry, Department of Pathology, University of California, 505 Parnassus Avenue, San Francisco, CA 94117, USA

		Arie.Perry@ucsf.edu

		
	
		Submitted: 30 November 2019

		Accepted: 07 December 2019

		Published: 01 January 2020

		 

		 https://doi.org/10.17879/fnp-2020-2611

		
	
		 

		
			
			If “a rose by any 
			other name would smell as sweet”, then does garbage by any other 
			name smell as foul? Before I argue the affirmative, I must first 
			fully disclose that like every other neuropathologist, I’ve 
			previously used the term “neuroepithelial tumor” in my own reports 
			and manuscripts. Nevertheless, I’ve been increasingly concerned that 
			its usage is now pursuing an alarming crescendo with an inversely 
			decreasing specificity.

			
			In the 2015 World 
			Health Organization (WHO) consensus meeting in Heidelberg, a 
			decision was made to abandon the term, “primitive neuroectodermal 
			tumor” or PNET from the subsequent 2016 scheme1 
			and this was generally hailed as a major breakthrough, with the 
			promise of enhancing our diagnostic accuracy for central nervous 
			system (CNS) tumor classification. Nonetheless, it was recognized 
			that even with improved definitions, one still encounters occasional 
			“PNET-like” cases that do not conform to currently known entities. 
			As such, it was decided to introduce the term, CNS embryonal tumor, 
			NOS for such cases. Of course, everyone recognized that this was 
			essentially trading in one trash can for another, but with the 
			notion that the new trash can was smaller and with the hope that as 
			additional entities are elucidated over time, eventually this 
			category would disappear altogether. Also, given that in 2013, the 
			soft tissue and bone blue book similarly ditched “peripheral PNET” 
			in favor of Ewing sarcoma2, 
			this new approach essentially eliminated the diagnosis of “PNET” 
			altogether.

			
			Unfortunately, 
			since the WHO 2016 publication1, 
			I feel that our trash can is yet again expanding, given that the 
			term “neuroepithelial tumor” (NET) is gaining momentum, both within 
			the literature and in clinical practice. For instance, whereas we 
			previously had only two known NET entities, dysembryoplastic 
			neuroepithelial tumor (DNET) (don’t even get me started on 
			“dysembryoplastic”) and cribriform neuroepithelial tumor (CRINET), 
			we’ve since added: 1) high-grade neuroepithelial tumor (HGNET) with
			MN1 alteration 
			(HGNET-MN1), 2) HGNET with 
			BCOR exon 15 internal tandem duplication (HGNET-BCOR), 3) 
			neuroepithelial tumor with H3 G34 mutation (NET-H3-G34), and 4) 
			polymorphous low-grade neuroepithelial tumor of the young (PLNTY)3-9. 
			Additionally, a fifth HGNET or HGNET, not elsewhere classified 
			(HGNET-NEC) is now being used in some clinical reports for malignant 
			CNS neoplasms that don’t fit neatly into a well-delineated tumor 
			type, although some of these descriptive diagnoses are eventually 
			replaced by a more specific one with further molecular testing.

			
			The Oxford 
			dictionary definition of neuroepithelium is: “1. A type of 
			epithelium containing sensory nerve endings and found in certain 
			sense organs (e.g. the retina, the inner ear, the nasal membranes, 
			and the taste buds)” or more pertinent to NET, “2. (in embryology) 
			ectoderm that develops into nerve tissue.” 
			https://www.lexico.com/en/definition/neuroepithelium). 
			Other definitions similarly focus on brain development. For 
			instance, according to Wikipedia, “neuroepithelial cells, or 
			neuroectodermal cells, form the wall of the closed neural tube in 
			early embryonic development. The neuroepithelial cells span the 
			thickness of the tube's wall, connecting with the pial surface and 
			with the ventricular or lumenal surface. They are joined at the 
			lumen of the tube by junctional complexes, where they form a 
			pseudostratified layer of epithelium called neuroepithelium. 
			Neuroepithelial cells are the stem cells of the central nervous 
			system, known as neural stem cells, and generate the intermediate 
			progenitor cells known as radial glial cells, that differentiate 
			into neurons and glia in the process of neurogenesis.” 
			(https://en.wikipedia.org/wiki/Neuroepithelial_cell). 
			This explains the intended use of neuroepithelial tumor in the 
			original 1988 description of DNET10, 
			wherein the authors emphasized their view that DNET is likely 
			related to a developmental disorder or malformation, given the 
			frequent histologic findings resembling focal cortical dysplasia in 
			adjacent cortex.

			
			In other 
			circumstances, NET is utilized in a broader fashion to state a 
			belief that a neoplasm is derived from CNS precursor cells. 
			Unfortunately, NET is now often utilized in an even less specific 
			manner, essentially meaning: “I think this is probably a CNS tumor 
			because it’s located there, but I wouldn’t swear to it under oath in 
			a court of law”. As long as the entire oncology team knows that this 
			diagnosis represents our mea culpa of ignorance, then there’s no 
			harm in using this term as a placeholder until we know more. 
			However, busy people (including oncologists) often generalize and 
			may assume that given the similar terminology, HGNET, NEC is 
			equivalent to HGNET-MN1 (replacing mostly what was previously 
			diagnosed as astroblastoma, mainly behaving as WHO grade II) or to 
			HGNET-BCOR and NET-H3-G34 (both behaving predominantly as WHO grade 
			IV tumors). In other words, one could falsely assume that all HGNETs 
			are biologically related and should therefore be treated in a 
			similar fashion clinically.

			
			Another major 
			source of confusion comes from very different uses of “NET” by 
			various experts. As already mentioned, in the past, it was an 
			abbreviation for neuroectodermal tumor within both central 
			and peripheral forms of PNET. In neuropathology, it is now being 
			used for neuroepithelial tumor as already discussed, but 
			outside the CNS, NET is currently utilized far more commonly as an 
			abbreviation for neuroendocrine tumor11. 
			This newly sanctioned WHO term represents the lower grade or well 
			differentiated subtype of “neuroendocrine neoplasm”. In other words, 
			this is the more favorable tumor type, but nevertheless one that 
			occasionally behaves more aggressively; in turn, NET needs to be 
			distinguished from neuroendocrine carcinoma, which is the overtly 
			malignant and high-grade form of disease. Within neuropathology, the 
			most common manifestation of this newly proposed nomenclature is the 
			pituitary neuroendocrine tumor or PitNET, in place of pituitary 
			adenoma12,13. 
			Nonetheless, with so many different versions now entering the 
			medical lexicon, no-one should be surprised if one NET subtype is 
			confused for another.

			
			In conclusion, by 
			discarding PNET (i.e., WHO grade IV small blue cell tumor with 
			neuronal features) in favor of NET or HGNET, have we essentially 
			exchanged our trash can for an industrial size dumpster? I 
			occasionally wake up in a sweat from dreaming of a dystopic future 
			wherein the WHO scheme is simply composed of a long list of entities 
			all entitled “neuroepithelial tumor with ___ molecular alteration”. 
			Wouldn’t it be preferable to go as far as we can with what we know? 
			In other words, if a tumor shows compelling astrocytic features, why 
			not invoke astrocytoma or astrocytic neoplasm in the name? If the 
			tumor has glioneuronal features, why not say so? If indeed, 
			neuroepithelial tumor is the best we can do, then at least, let’s 
			make a concerted effort to replace the name once we know more. Of 
			course, this is just one man’s opinion and an opinion is only worth 
			the price one pays for it!

		

		
			
			References

		

		
		
		
		1.      
		Louis 
		DN, Ohgaki H, Wiestler OD, et al. WHO 
		classification of tumours of the central nervous system (Revised 4th 
		edition). Lyon, France: IARC; 2016.

		
		
		
		2.      
		Fletcher CDM, Bridge 
		JA, Hogendoorn PCW, Mertens F, eds. WHO Classification of Tumours of 
		Soft Tissue and Bone. 4th ed. Lyon, France: IARC; 2013.

		
		
		
		3.      
		Sturm D, Orr BA, 
		Toprak UH, et al. New Brain Tumor Entities Emerge from Molecular 
		Classification of CNS-PNETs. Cell. 2016;164(5):1060-1072.

		
		
		
		4.      
		Korshunov A, Capper D, 
		Reuss D, et al. Histologically distinct neuroepithelial tumors with 
		histone 3 G34 mutation are molecularly similar and comprise a single 
		nosologic entity. Acta Neuropathol. 2016;131(1):137-146.

		
		
		
		5.      
		Paret C, Theruvath J, 
		Russo A, et al. Activation of the basal cell carcinoma pathway in a 
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		targeted therapy. Oncotarget. 2016;7(50):83378-83391.

		
		
		
		6.      
		Yoshida Y, Nobusawa S, 
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		soft tissue. Brain Pathol. 2018;28(5):710-720.

		
		
		
		7.      
		Huse JT, Snuderl M, 
		Jones DT, et al. Polymorphous low-grade neuroepithelial tumor of the 
		young (PLNTY): an epileptogenic neoplasm with oligodendroglioma-like 
		components, aberrant CD34 expression, and genetic alterations involving 
		the MAP kinase pathway. Acta Neuropathol. 2017;133(3):417-429.

		
		
		
		8.      
		
		Ferris SP, Velazquez Vega 
		J, Aboian M, et al. High-grade neuroepithelial 
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		(in press).

		
		
		
		9.      
		Andreiuolo F, Lisner 
		T, Zlocha J, et al. H3F3A-G34R mutant high grade neuroepithelial 
		neoplasms with glial and dysplastic ganglion cell components. Acta 
		Neuropathol Commun. 2019;7(1):78.

		
		
		
		10.   
		Daumas-Duport C, 
		Scheithauer BW, Chodkiewicz JP, Laws ER, Jr., Vedrenne C. 
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		cases. Neurosurgery. 1988;23(5):545-556.

		
		
		
		11.   
		Rindi G, Klimstra DS, 
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		Mod Pathol. 2018;31(12):1770-1786.

		
		
		
		12.   
		
		Asa SL, Casar-Borota O, 
		Chanson P, et al. From pituitary adenoma to 
		pituitary neuroendocrine tumor (PitNET): an International Pituitary 
		Pathology Club proposal. Endocr Relat Cancer. 2017;24(4):C5-C8.

		
		
		
		13.   
		
		Villa C, Vasiljevic A, 
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		diagnostic approach to pituitary neuroendocrine tumours (PitNETs): a 
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		2019;475(6):687-692.

		
		 

		


	

