Classification tool for the systematic histological assessment of hepatocellular carcinoma, macroregenerative nodules, and dysplastic nodules in cirrhotic liver

Table 1 Scheme for the systematic assessment of histological features in liver cell nodules in cirrhotic livers

Feature	Modality of assessment
Nodule maximum diameter			Measurement in millimeter
Solitary arterioles			Average of individual arteries ×100 (medium power field, MPF) fields
Mitotic activity			Number of mitoses per 10 ×400 (10 high power fields, 10 HPF) fields
Trabecular thickness			Number of liver cells forming trabecular (LCT) width
Vascular invasion					Present/absent
Capsular invasion					Present/absent
Necrosis2				Present/absent
Nodule heterogeneity1				Present/absent
Reticulin loss3	None	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Capillarization (CD34)3	None	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Cellular atypia3	None	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5

¹Phenotypically recognizable “clonal” changes e.g. clear cell change, fatty change, microacinar structures;

²excluding post-treatment necrosis;

³see text pages 5-6.

Table 3 Classification tool for hepatocellular lesions in cirrhotic liver. Assess each individual histological feature (as per Table 1) and go to Table 4a

Column 1	Column 2	Column 3	Column 4
HCC	DN or MRN	DN	MRN
	Vascular invasion not present	Capillarization score 3, 4, or 5	Capillarization score 0, 1, or 2
	Capsular invasion not present	Cellular atypia score 1, 2, 3, 4, or 5	Cellular atypia score 0
Necrosis present	Necrosis not present	Reticulin loss score 1, 2, 3, 4, or 5	Reticulin loss score 0
Mitosis present	Mitosis not present	Trabecular thickness >3	Trabecular thickness <4
Capillarization score 4 or 5	Capillarization Score 0, 1, 2 or 3	Solitary arterioles ≥1	Solitary arterioles <1
Cellular atypia score 3, 4, or 5	Cellular atypia score 0, 1, or 2	Heterogeneity present	Heterogeneity absent
Reticulin loss score 1, 2, 3, 4, or 5	Reticulin loss score 0	Necrosis present
Trabecular thickness>3	Trabecular thickness<4	Mitosis present
Solitary arterioles ≥1	Solitary arterioles<1
Heterogeneity present	Heterogeneity absent

3a HCC vs DN/MRN If the given lesion is not HCC according to this table, Table 3b provides guidance regarding the assignment of DN vs MRN. 3b DN vs MRN. The nodule is DN, if the number of features in the “DN, column 3” is higher than the number of the features in the “MRN, column 4” and vice versa. In case of an even balance, the nodule is regarded as DN HCC, hepatocellular carcinoma; DN, dysplastic nodule; MRN, macroregenerative nodule.

Table 2 MCA of the values of the histological variables in the three categories (HCC, MRN, and DN) in the exploratory set of 212 hepatocellular nodules in cirrhotic livers

Position	Feature	Grade	HCC number (total 106)	%	DN number (total 32)	%	MRN number (total 74)	%
1	Vascular invasion	Present	27	25.5	0	0	0	0
2	Necrosis	Present	17	16	0	0	0	0
3	Capsular invasion	Present	44	41.5	0	0	0	0
4	Cellular atypia	4-5	30	28.3	0	0	0	0
5	Trabecular thickness	>4	35	33	1	3	0	0
6	Mitosis	Any	50	47.2	0	0	0	0
7	Reticulin loss	4-5	47	44.3	0	0	0	0
8	Capillarization	5	56	52.8	0	0	0	0
9	Cellular atypia	3	38	35.8	0	0	0	0
10	Solitary arterioles	>2	23	21.7	1	3	1	1
11	Trabecular thickness	4	27	25.5	3	9	0	0
12	Capillarization	4	27	25.5	1	3	0	0
13	Solitary arterioles	2	37	34.9	5	15	1	1
14	Heterogeneity	Present	100	94.3	23	72	5	7
15	Reticulin loss	1-3	56	52.8	9	28	2	3
16	Solitary arterioles	1	33	31.1	7	22	10	14
17	Capillarization	3	19	17.9	8	25	2	3
18	Trabecular thickness	<4	44	41.5	27	84	72	97
19	Cellular atypia	1-2	37	34.9	12	38	16	22
20	Necrosis	Not present	89	84	32	100	74	100
21	Vascular invasion	Not present	79	74.5	32	100	74	100
22	Capsular invasion	Not present	62	58.5	32	100	74	100
23	Mitosis	Not present	56	52.8	32	100	74	100
24	Solitary arterioles	<1	13	12.3	19	59	62	84
25	Capillarization	0–2	4	3.8	23	72	72	97
26	Cellular atypia	0	1	0.9	20	63	58	78
27	Heterogeneity	Not present	6	5.7	9	28	69	93
28	Reticulin loss	0	3	2.8	23	72	72	97

Position = This means the position of each variable in “malignancy scale” as shown in Figure 2, i.e. position number 1 = left side of the chart (higher “degree of malignancy”) and position 28 = right side of the chart (lower degree of malignancy).

Table 4 Performance of the classification tool on a second validation set of liver cell nodules in cirrhotic livers

				Histological assessment usingthe classification tool
			HCC	DN	MRN	Total
Routine	HCC	25	17	8	0	25
Histologica	lDN	9	0	9	0	9
Diagnosis	MRN	13	0	0	13	13
	Total		17	17	13	Total