Neuroendocrine neoplasms의 grading 평가 (mitotic activity, Ki-67 labeling index)

세계보건기구(WHO)의 위장췌장 신경내분비종양(gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs)) 분류는 저등급, 중등급, 고등급 종양을 구분하기 위해 증식률 (proliferative rate)에 전적으로 의존하고 있습니다. Proliferative rate는 mitotic counts 또는 Ki-67 labeling index를 이용하여 평가합니다.

Mitotic count에 의존하는 모든 등급체계에서, low grade와 intermediate grade 사이의 구별은 미묘하고 HPF 당 단지 1개의 nitotic figure에 달려 있을 수 있습니다. 따라서 mitoses를 정확하게 세는 것이 매우 중요합니다. ​ It is recommended that only clear-cut mitotic figures be counted, excluding degenerating dark-stained nuclei and apoptotic bodies. ​ 10 HPF 크기는 표준화를 위해 2 m㎡로 정해져 있습니다.

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2010 ENETS/WHO nomenclature and classification과 다르게 World Health Organization (WHO), 2019 classification and grading criteria에는 다음과 같이 high-grade이지만 well-differentiated GEP NENs 개념이 포함되어 있습니다.

NET, G3

Well differentiated

High

>20

>20

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Classification and grading criteria for neuroendocrine neoplasms of the gastrointestinal tract and hepatobiliary organs, World Health Organization (WHO), 2019

Terminology	Differentiation	Grade	Mitotic rate* (mitoses/2 mm2)	Ki-67 index* (percent)
NET, G1	Well differentiated	Low	<2	<3
NET, G2	Well differentiated	Intermediate	2 to 20	3 to 20
NET, G3	Well differentiated	High	>20	>20
NEC, small cell type (SCNEC)	Poorly differentiated	HighΔ	>20	>20
NEC, large cell type (LCNEC)	Poorly differentiated	HighΔ	>20	>20
MiNEN	Well or poorly differentiated¶	Variable¶	Variable¶	Variable¶

NET: neuroendocrine tumor; NEC: neuroendocrine carcinoma; SCNEC: small cell neuroendocrine carcinoma; LCNEC: large cell neuroendocrine carcinoma; MiNEN: mixed neuroendocrine-nonneuroendocrine neoplasm.

* Mitotic rates are to be expressed as the number of mitoses/2 mm2 (equalling 10 high-power fields at 40× magnification and an ocular field diameter of 0.5 mm) as determined by counting in 50 fields of 0.2 mm2 (ie, in a total area of 10 mm2); the Ki-67 proliferation index value is determined by counting at least 500 cells in the regions of highest labelling (hot-spots), which are identified at scanning magnification; the final grade is based on whichever of the two proliferation indexes places the neoplasm in the higher grade category.

¶ In most MiNENs, both the neuroendocrine and nonneuroendocrine components are poorly differentiated, and the neuroendocrine component has proliferation indexes in the same range as other NECs, but this conceptual category allows for the possibility that one or both components may be well differentiated; when feasible, each component should therefore be graded separately.

Δ Poorly differentiated NECs are not formally graded but are considered high grade by definition

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2010 ENETS/WHO nomenclature and classification for neuroendocrine neoplasms arising in the gastrointestinal (GI) tract

Differentiation	Grade	Mitotic count*	Ki-67 index¶	Traditional	ENETS, WHO
Well differentiated	Low grade (G1)	<2 per 10 HPF	<3%	Carcinoid, islet cell, pancreatic (neuro)endocrine tumor	Neuroendocrine tumor, G1
	Intermediate grade (G2)	2 to 20 per 10 HPF	3 to 20%	Carcinoid, atypical carcinoidΔ, islet cell, pancreatic (neuro)endocrine tumor	Neuroendocrine tumor, G2
Poorly differentiated	High grade (G3)	>20 per 10 HPF	>20%	Small cell carcinoma	Neuroendocrine carcinoma, G3, small cell
				Large cell neuroendocrine carcinoma	Neuroendocrine carcinoma, G3, large cell

ENETS: European Neuroendocrine Tumor Society; WHO: World Health Organization; HPF: high-power fields.

* Counted in 10 HPF; 10 HPF = 2 mm2, at least 40 fields (at 400x magnification) evaluated in areas of highest mitotic density. Cut-offs per American Joint Commission on Cancer Staging Manual, 8th edition.

¶ Ki-67 index as assessed by MIB1 antibody staining: percent positive after count of 2000 cells in area of highest nuclear labeling. Cut-offs per American Joint Commission on Cancer Staging Manual, 8th edition.

Δ The term "atypical carcinoid" only applies to intermediate-grade neuroendocrine tumors of the lung.

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REF. UpToDate 2020.08.26