Mixed neuroendocrine–nonneuroendocrine neoplasms of the gastrointestinal system: An update

Table 1 Discrimination among mixed neuroendocrine-nonneuroendocrine neoplasms, neuroendocrine tumors, and carcinomas according to pathological parameters

Morphology	Dual differentiation present			Dual differentiation absent
Immunohistochemisty
Neuroendocrine markers	(-)	(+)	(+)	(+)	(-)	Few (+) cells1
Nonneuroendocrine markers	(+)	Few (+) cells	(+)	(+)	(+)	(+)
Diagnosis	Carcinoma	NEN	MiNEN	Amphicrine tumor	Carcinoma	Carcinoma

¹These cells frequently express synaptophysin, the expression of other neuroendocrine markers is rare.

NEN: Neuroendocrine neoplasia.

Table 2 Classification of mixed neuroendocrine-nonneuroendocrine neoplasms depending on the grade of malignancy[15]

Grade of MiNEN	Nonneuroendocrine component	Endocrine component
High-grade	Adenocarcinoma	PDNEC, NET G31
	Squamous cell carcinoma
	Cholangiocarcinoma
	Ductal and acinar cell carcinoma
	Ductal adenocarcinoma
High-grade	Acinar cell carcinoma	NET, G1 or G21
	Ductal adenocarcinoma
	Acinar cell carcinoma
Intermediate grade	Adenocarcinoma	NET, G1 or G21
Low-grade2	Adenoma	NET, G1 or G2

¹Grading should be performed according to the latest WHO classification.

²Those tumors are not included in the mixed neuroendocrine-nonneuroendocrine neoplasms category.

MiNEN: Mixed neuroendocrine-nonneuroendocrine neoplasms; PDNEC: Poorly differentiated neuroendocrine carcinoma; G: Grade; NET: Neuroendocrine tumor.

Table 3 Summary of the therapy protocols applied to localized mixed neuroendocrine-nonneuroendocrine neoplasms

Surgery	Complete resection is possible			Complete resection is not possible
MiNEN grade	High	Intermediate	Low	High	Intermediate	Low
Chemotherapy	PDNEC-like	ADC-like	NR	PDNEC-like	ADC- like	NET-like

MiNEN: Mixed neuroendocrine-nonneuroendocrine neoplasms; ADC: Adenocarcinoma; PDNEC: Poorly differentiated neuroendocrine carcinoma; NET: Neuroendocrine tumor.

Table 4 Summary of the therapy protocols applied to metastatic mixed neuroendocrine-nonneuroendocrine neoplasms

Metastatic component	Defined		Not defined
	One component	Two components
Chemotherapy target	The metastatic component	The most aggressive component	The most aggressive component in the primary tumor