Clinicopathological Features of Hepatocellular Carcinoma with Metabolic Risk Factors

Figures & data

Figure 1 Flow chart of the study participants.

Figure 2 The degrees of surrounding nontumoral liver tissue steatosis in MAFLD-related HCC with liver cirrhosis background (A) and non-cirrhosis background (B), which are less than 30% (hematoxylin and eosin stain, original magnification ×100).

Table 1 Comparison Between Different Groups

	HCC with Metabolic Risk Factors (32 Cases)	HCC Without Metabolic Risk Factors (10 Cases)	P value	MAFLD-Related HCC (20 Cases)	HCC with Only Metabolic Risk Factors (12 Cases)	P value
Age(years)	63.2±11.4	51.8±18.6	0.023	62.8±12.2	63.8±10.3	0.808
Sex (M/F)	21/11	6/4	0.746	13/7	8/4	0.923
Liver cirrhosis(cases)	13 (40.6%)	5 (50.0%)	0.601	11 (55.0%)	2 (16.7%)	0.033
Obesity (BMI≥23) (cases)	8 (25.0%)	0	0.079	6 30.0%)	2 (16.7%)	0.399
T2DM (cases)	25 (78.1%)	0	0.000	18 (90.0%)	7 (58.3%)	0.036
Hypertension(cases)	23 (71.9%)	1 10.0%)	0.001	14 (70.0%)	9 (75.0%)	0.761
Blood triglyceride level ≥1.70 mmol/L (cases)	10 (31.3%)	0	0.043	6 (30.0%)	4 (33.3%)	0.844
HDL-C level <1.0 mmol/L in males and 1.3 mmol/L in females(cases)	24 (75.0%)	7 (70.0%)	0.754	16 (80.0%)	8 (66.7%)	0.399
Elevated CRP (>6mg/L) (cases)	11 (34.4%)	4 (40.0%)	0.746	5 (25.0%)	6 (50.0%)	0.149
Elevated AFP (>8.78 g/mL) (cases)	12 (37.5%)	6 (60.0%)	0.209	8 (40.0%)	4 (33.3%)	0.706
Trabecular type(cases)	13 (40.6%)	4 (40.0%)	0.972	10 (50.0%)	3 (25.0%)	0.163
Steatohepatitic type(cases)	9(28.1%)	2 (20.0%)	0.610	7 (35.0%)	2 (16.7%)	0.264
Scirrhous type(cases)	4(12.5%)	1 (10.0%)	0.831	0	4 (33.3%)	0.006
Solid type(cases)	2(6.3%)	0	0.418	1 (5.0%)	1 (8.3%)	0.706
Pseudoglandular type(cases)	2(6.3%)	0	0.418	1(5.0%)	1 (8.3%)	0.706
Clear cell type(cases)	1(3.1%)	0	0.572	0	1(8.3%)	0.190
Macrotrabecular type(cases)	1(3.1%)	3 (30.0%)	0.012	1 (5.0%)	0	0.431
ALT (U/L)	42.5±56.0	38.6±27.3	0.830	36.1±20.8	53.3±88.9	0.409
AST (U/L)	42.1±38.7	63.7±44.5	0.145	36.7±19.3	51.1±58.6	0.316
AKP (U/L)	121.5±102.2	151.1±113.1	0.442	96.3±67.8	161.3±134.7	0.142
GGT (U/L)	134.8±167.5	127.1±150.1	0.898	118.2±187.9	160.9±132.3	0.499
TBIL (umol/L)	15.6±7.5	18.9±7.8	0.233	17.6±8.4	12.3±4.0	0.053
DBIL (umol/L)	7.05±5.47	9.56±5.70	0.217	8.16±6.51	5.19±2.21	0.139
TBA (umol/L)	12.0±16.9	53.8±68.0	0.085	14.9±21.0	7.4±3.8	0.142
TCHO (mmol/L)	4.36±1.50	3.53±1.36	0.133	4.11±1.14	4.84±2.02	0.222
TG (mmol/L)	1.42±0.69	0.77±0.35	0.001	1.36±0.55	1.54±0.93	0.587
HDL-C (mmol/L)	0.94±0.39	1.08±0.44	0.335	0.89±0.29	1.04±0.53	0.332
LDL-C (mmol/L)	2.74±1.19	1.96±0.68	0.058	2.63±0.98	2.95±1.56	0.503
APO-A1 (g/L)	1.14±0.34	1.13±0.38	0.959	1.11±0.23	1.20±0.49	0.521
APO-B (g/L)	0.85±0.35	0.60±0.19	0.040	0.80±0.26	0.95±0.47	0.262
LP(a)(mg/dL)	18.7±25.2	7.3±15.2	0.192	10.6±13.9	36.9±35.3	0.076
GLU (mmol/L)	7.09±3.52	5.17±0.67	0.006	7.28±3.68	6.78±3.37	0.707
ALB (g/L)	38.8±5.5	38.0±5.3	0.713	39.0±5.2	38.3±6.1	0.723
GLO (g/L)	28.0±5.3	28.1±5.5	0.983	27.6±5.2	28.7±5.6	0.569

Abbreviations: HCC, hepatocellular carcinoma; MAFLD, metabolic associated fatty liver disease; T2DM, type 2 diabetes mellitus; CRP, C-reactive protein; AFP, Alpha-FetoProtein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AKP, alkaline phosphatase; GGT, γ-glutamyl transpeptidase; TBiL, total bilirubin; DBiL, direct bilirubin; TBA, total bile acid; TCHO, total cholesterol; TG, triglycerides; HDL-C, high-density liptein cholesterol; LDL-C, low-density liptein cholesterol; APO-A1, apolipoprotein A1; ApoB, apolipoprotein B; LPa, lipoprotein(a); GLU, Glucose; ALB, albumin; GLO, Globularproteins.

Figure 3 HCC with metabolic risk factor architectural growth patterns: (A) The tumor cells grow in trabecular pattern. (B) The tumor cells grow in a macrotrabecular pattern with thick trabeculae more than 10 cell layers. (C) The tumor cells grow in a pseudoglandular pattern with glandular or acinar structure. (D) The tumor cells grow in a solid pattern without trabecular or pseudoglandular growth. (hematoxylin and eosin stain, original magnification ×100).

Figure 4 Major subtypes of HCC with metabolic risk factors. (A) Steatohepatitic HCC: The tumor shows macrovesicular steatosis, ballooning, Mallory–Denk bodies, and inflammation (hematoxylin and eosin stain, original magnification ×100). (B) Scirrhous HCC: The tumor nests and single tumor cells are present in a dense desmoplastic background (hematoxylin and eosin stain, original magnification ×200). (C) Clear-cell HCC: The tumor cells have glycogen-rich clear cytoplasm (hematoxylin and eosin stain, original magnification ×200).

Figure 5 Histological features of steatohepatitic HCC. (A) Tumor cells with a group of ballooning hepatocytes with enlarged, rounded, rarefied cytoplasm, with some hepatocytes containing Mallory–Denk bodies (marked by arrow) (hematoxylin and eosin stain, original magnification ×400). (B) Glycogenated nuclei can be seen in some tumor cells (marked by arrow) (hematoxylin and eosin stain, original magnification ×200).

Table 2 Pathological Characteristics and Laboratory Indicators Between Different Pathological Types of HCC with Metabolic Risk Factors

	Trabecular Type (13 Cases)	Steatohepatitis Type (9 Cases)	Scirrhous Type (4 Cases)	Other four Types (6 Cases)
Age(years)	62.1±14.6	63.3±6.9	62.3±16.2	66.0±6.4
Sex (M/F)	8/5 (0.687)	6/3	3/1	4/2
Inflammation score in surrounding liver tissue	2.5 (1.875,3) *	1.75 (1.5,2)	1.5 (1,2)	1.75 (1.125,2)
Fibrosis score in surrounding liver tissue	2.75 (2,3.625)	4 (3.875,5)*	3 (3,4)	2 (0.75,1.25)
Steatosis in surrounding liver tissue	8% (0,10%)	5% (2.5%,12.5%)	0 (0,0)^#	0 (0,12.5%)
Swelling and ballooning of tumor cells (%)	0 (0,10%) ^#	40% (35%,60%)*	25% (2.5%,55%)	0 (0,17.5%)
Mallory-Denk body(cases)	3/13 (23.1) ^#	9/9 (100%) *	3/4 (75%)	2/6 (33.3%)
TCHO (mmol/L)	5.18±1.89*	3.73±0.98	3.20±0.65	4.62±0.72
TP (g/L)	70.0±6.1	62.3±5.1	60.2±12.0	71.1±4.1
WBC (109/L)	6.29±3.81	3.96±1.76^#	9.26±2.84	6.66±1.70
RBC (1012/L)	4.31±0.84	3.56±0.49^#	3.89±1.18	4.73±0.32
Hb (g/L)	133.5±25.1	108.6±22.7^#	113.0±34.2	142.0±22.1

Note: * significantly higher than those in other types (p < 0.05). ^# markedly lower than those in other types (p < 0.05).

Abbreviations: TCHO, total cholesterol; TP, Total Protein; WBC, White blood cell; RBC, Red blood cell; Hb, Hemoglobin.

Table 3 Correlation Analysis Between Pathological Characteristics and Laboratory Indicators of HCC with Metabolic Risk Factors

	Swelling and Ballooning of Tumor Cells		Steatosis in Surrounding Liver Tissue		Inflammation in Surrounding Liver Tissue		Fibrosis in Surrounding liver Tissue		Cirrhosis		CK19		HepPar1		GPC3		HSP70
	r value	P value	r value	p value	r value	p value	r value	p value	r value	p value	r value	p value	r value	p value	r value	p value	r value	p value
Differentiation of HCC	0.058	0.754	−0.202	0.275	−0.072	0.799	0.441	0.100	−0.084	0.647	0.770	0.000	−0.375	0.041	−0.281	0.126	0.130	0.632
Cirrhosis	0.499	0.004	0.254	0.167	0.000	1.000	0.820	0.000	–	–	−0.112	0.564	−0.025	0.894	0.464	0.009	0.491	0.053
Obesity	−0.033	0.860	0.215	0.245	0.000	1.000	0.080	0.776	0.110	0.548	0.012	0.950	−0.209	0.267	0.013	0.946	0.029	0.915
T2DM	−0.034	0.853	0.238	0.197	0.062	0.826	−0.020	0.944	0.130	0.479	−0.125	0.518	−0.063	0.741	−0.098	0.599	−0.169	0.531
Hypertension	0.173	0.345	0.096	0.609	−0.211	0.451	−0.100	0.722	−0.049	0.791	−0.510	0.005	0.357	0.053	0.262	0.155	0.196	0.467
Elevated TG level	−0.323	0.071	−0.336	0.065	−0.311	0.260	−0.197	0.481	−0.420	0.017	−0.045	0.815	0.192	0.310	−0.008	0.966	−0.166	0.539
Decreased HDL-C level	0.208	0.254	0.131	0.481	−0.585	0.022	0.302	0.275	0.037	0.842	−0.100	0.607	0.357	0.053	−0.072	0.701	0.231	0.389
ALT	−0.051	0.761	−0.072	0.721	0.040	0.887	−0.161	0.567	0.021	0.911	−0.355	0.059	0.034	0.858	0.260	0.158	0.499	0.049
AST	0.015	0.934	−0.242	0.223	0.253	0.363	−0.018	0.949	0.024	0.896	−0.002	0.992	−0.163	0.390	0.063	0.738	0.123	0.650
AKP	−0.227	0.219	−0.555	0.003	0.397	0.143	−0.225	0.421	−0.336	0.064	0.192	0.328	−0.140	0.468	0.019	0.920	0.299	0.279
GGT	−0.097	0.603	−0.386	0.047	0.115	0.683	0.124	0.659	−0.117	0.531	0.093	0.637	−0.022	0.911	−0.053	0.781	0.409	0.130
TBil	−0.019	0.920	0.294	0.137	−0.012	0.968	0.184	0.511	0.389	0.028	−0.074	0.703	−0.066	0.728	0.267	0.147	0.517	0.040
DBiL	0.169	0.356	0.164	0.413	−0.069	0.807	0.403	0.137	0.396	0.025	−0.010	0.958	−0.076	0.690	0.252	0.171	0.614	0.011
TCHO	−0.442	0.016	−0.041	0.864	0.311	0.260	−0.741	0.002	−0.456	0.013	0.014	0.946	−0.024	0.907	−0.301	0.119	−0.520	0.047
LDL-C	−0.493	0.007	0.057	0.786	0.167	0.552	−0.726	0.002	−0.497	0.006	0.078	0.705	0.002	0.992	−0.317	0.100	−0.496	0.060
APO-A1	−0.381	0.041	0.094	0.655	0.115	0.683	−0.647	0.009	0.050	0.798	−0.114	0.581	−0.104	0.606	0.067	0.736	−0.233	0.404
APO-B	−0.428	0.020	0.048	0.819	0.167	0.552	−0.586	0.022	−0.510	0.005	0.132	0.520	−0.032	0.876	−0.363	0.057	−0.542	0.037
LP(a)	−0.073	0.723	−0.551	0.008	0.570	0.033	−0.177	0.544	−0.252	0.214	0.335	0.102	−0.397	0.055	−0.416	0.039	−0.294	0.307
GLU	0.048	0.794	0.097	0.629	0.213	0.446	−0.062	0.826	−0.031	0.866	−0.027	0.888	0.115	0.547	−0.389	0.031	−0.253	0.344
TP	−0.534	0.002	−0.128	0.524	0.371	0.173	−0.613	0.015	−0.403	0.022	−0.073	0.707	0.087	0.647	−0.050	0.789	−0.310	0.243
AFP	−0.273	0.130	−0.016	0.938	0.224	0.422	0.153	0.585	0.114	0.535	−0.033	0.865	−0.026	0.891	0.446	0.012	0.488	0.055
WBC	−0.471	0.007	−0.281	0.156	−0.265	0.341	−0.672	0.006	−0.596	0.000	0.313	0.099	−0.171	0.368	−0.231	0.212	0.076	0.780
RBC	−0.607	0.000	0.040	0.845	−0.207	0.459	−0.464	0.082	−0.296	0.100	0.134	0.487	0.071	0.708	0.021	0.910	−0.052	0.847
Hb	−0.665	0.000	−0.044	0.828	−0.012	0.968	−0.276	0.320	−0.276	0.127	0.022	0.908	0.045	0.815	0.075	0.690	0.059	0.828
PLT	−0.337	0.034	−0.061	0.764	−0.115	0.683	−0.613	0.015	−0.741	0.000	0.057	0.770	0.092	0.630	−0.382	0.034	−0.074	0.784

Abbreviations: CK19, Cytokeratin 19; GPC-3, glypican-3; HSP70, heat shock protein 70; HCC, hepatocellular carcinoma; T2DM, type 2 diabetes mellitus; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AKP, alkaline phosphatase; GGT, γ-glutamyl transpeptidase; TBiL, total bilirubin; DBiL, direct bilirubin; TCHO, total cholesterol; LDL-C, low-density liptein cholesterol; APO-A1, apolipoprotein A1; ApoB, apolipoprotein B; LPa, lipoprotein(a); GLU, Glucose; TP, Total Protein; AFP, Alpha-FetoProtein; WBC, White blood cell; RBC, Red blood cell; Hb, Hemoglobin; PLT, platelet.

Table 4 Comparison of Liver Cirrhosis and Non-Cirrhosis Patients with HCC with Metabolic Risk Factors

	Cirrhosis (13 Cases)	No Cirrhosis (19 Cases)	P value
Age(years)	63.5±10.2	63.0±12.4	0.912
Sex (M/F)	6/7	15/4	0.055
Obesity (BMI≥23) (cases)	4 (30.8%)	4 (21.1%)	0.533
T2DM (cases)	11 (84.6%)	14 (73.7%)	0.463
Hypertension(cases)	9 (69.2%)	14 (73.7%)	0.783
Blood triglyceride level ≥1.70 mmol/L (cases)	1 (7.7%)	9 (47.4%)	0.017
HDL-C level <1.0 mmol/L in males and 1.3 mmol/L in females(cases)	10 (76.9%)	14 (73.7%)	0.835
Elevated CRP (>6mg/L) (cases)	2/13 (15.4%)	9/19 (47.4%)	0.061
Elevated AFP (>8.78 g/mL) (cases)	7/13 (53.8%)	5/19 (26.3%)	0.114
Swelling and ballooning tumor cells	20% (10%,50%)	0 (0,40%)	0.007
Mallory-Denk body(cases)	11 (84.6%)	6 (31.6%)	0.003
Glycogenated nuclei(cases)	8 (61.5%)	4 (21.1%)	0.020
GPC3 expression	2 (1, 2.25)	0 (0, 1.5)	0.008
ALT (U/L)	35.2±20.0	47.5±71.2	0.549
AST (U/L)	36.7±18.4	45.8±48.1	0.524
AKP (U/L)	87.6±58.0	145.9±120.7	0.086
GGT (U/L)	142.1±219.1	129.5±124.7	0.840
TBIL (umol/L)	19.5±9.5	12.9±4.2	0.034
DBIL (umol/L)	9.35±7.37	5.47±2.96	0.092
TBA (umol/L)	15.7±19.3	9.3±14.8	0.304
TCHO (mmol/L)	3.66±0.98	4.93±1.63	0.020
TG (mmol/L)	1.12±0.35	1.67±08.0	0.022
HDL-C (mmol/L)	1.00±0.39	0.90±0.39	0.505
LDL-C (mmol/L)	2.15±0.64	3.23±1.33	0.012
APO-A1 (g/L)	1.19±0.35	1.10±0.33	0.487
APO-B (g/L)	0.66±0.17	1.00±0.38	0.007
LP(a)(mg/dL)	11.4±13.8	25.0±31.1	0.157
GLU (mmol/L)	7.03±3.64	7.14±3.54	0.933
TP (g/L)	63.9±5.5	68.8±8.2	0.072
ALB (g/L)	37.9±3.6	39.4±6.5	0.420
GLO (g/L)	26.0±5.8	29.4±4.5	0.073
WBC (10^9/L)	4.02±1.68	7.48±3.29	0.002
RBC (10^12/L)	3.89±0.67	4.29±0.89	0.178
Hb (g/L)	119.3±22.8	129.8±30.0	0.295
PLT (10^9/L)	95.2±31.5	201.1±83.0	0.000

Abbreviations: HCC, hepatocellular carcinoma; T2DM, type 2 diabetes mellitus; CRP, C-reactive protein; AFP, Alpha-FetoProtein; GPC-3, glypican-3; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AKP, alkaline phosphatase; GGT, γ-glutamyl transpeptidase; TBiL, total bilirubin; DBiL, direct bilirubin; TBA, total bile acid; TCHO, total cholesterol; TG, triglycerides; HDL-C, high-density liptein cholesterol; LDL-C, low-density liptein cholesterol; APO-A1, apolipoprotein A1; ApoB, apolipoprotein B; LPa, lipoprotein(a); GLU, Glucose; TP, Total Protein; ALB, albumin; GLO, Globularproteins; WBC, White blood cell; RBC, Red blood cell; Hb, Hemoglobin; PLT, platelet.