Quantitative Assessment of Hypovascular Component in Arterial Phase to Help the Discrimination of Combined Hepatocellular-Cholangiocarcinoma and Hepatocellular Carcinoma

Figures & data

Figure 1 Flowchart demonstrating recruitment pathway for the population.

Abbreviations: cHCC‐CCA, combined hepatocellular‐ cholangiocarcinoma; HCC, hepatocellular carcinoma; CT, computed tomography; MRI, magnetic resonance imaging.

Table 1 Comparison of Clinico-Pathological Features Between cHCC-CCA and HCC

Variable	cHCC-CCA (n = 35)	HCC (n = 35)	P value
Clinical findings
Age(years)	54.2±8.156	52.86±11.39	0.323
Gender (Male [%])	26 (74.3%)	30 (85.7%)	0.232
Etiology (%)
None	5 (14.3%)	1 (2.9%)	0.289
HBV	28 (80%)	32 (91.4%)
HCV	2 (5.7%)	2 (5.7%)
Child-Pugh classification (A [(%])	33 (94.3%)	33 (94.3%)	1.000
Cirrhosis (%)	17 (48.6%)	18 (51.4%)	0.811
AFP (>20 ng/mL [%])	15 (42.9%)	16 (45.7%)	0.810
CA19-9 (>37 U/mL [%])	13 (37.1%)	4 (11.4%)	0.012*
ALT (U/L)	22 (19–38)	26 (19–39)	0.335
AST (U/L)	26 (21–37)	26 (22–35)	0.698
TBIL (umol/L)	14.6 (11.3–22.9)	15.7 (13–20.2)	0.545
DBIL (umol/L)	4.6 (3.4–7.1)	5.2 (4.1–7.1)	0.381
Albumin (g/l)	41.66±3.88	40.84±4.92	0.144
GGT (U/L)	39.5 (25–62)	30 (20–49)	0.298
PT (sec)	11.7 (11.1–12.5)	12 (11.5–12.9)	0.111
PLT (*10^9 /L)	164 (116–224)	152 (118–219)	0.283
Pathological features
Tumor number (%)	33 (94.3%)	34 (97.1%)	1.000
Tumor size (≥50mm [%])	15 (42.9%)	7 (20%)	0.070
Tumor necrosis	14 (40%)	10 (28.6%)	0.314
Vascular invasion (%)	16 (45.7%)	19 (54.3%)	0.631
MVI (%)	18 (51.4%)	20 (57.1%)	0.631
Macrovascular invasion (%)	2 (5.7%)	3 (8.6%)	1.000
Satellite nodules (%)	13 (37.1%)	5 (14.3%)	0.029*
Macrotrabecular appearance	9 (25.71%)	2 (5.71%)	0.022*
CK19	30 (85.7%)	6 (17.1%)	0.000*
Hepa-1	26 (74.3%)	33 (94.3%)	0.022*
GPC-3	26 (74.3%)	29 (82.9%)	0.382
CK7	29 (82.9%)	9 (25.7%)	0.000*

Notes: According to whether the data conforms to the normal distribution, continuous variables are presented as median (range) or mean±standard deviation and analyzed using independent t-test or Mann–Whitney U-test. Categorical variables are expressed by number and percentage and compared by Pearson’s χ² test or Continuity Correction or Fisher’s exact test. *p<0.05.

Abbreviations: cHCC‐CCA, combined hepatocellular‐ cholangiocarcinoma; HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV,hepatitis C virus; AFP, alpha-fetoprotein; CA19-9, carbohydrate antigen-199; ALT, alanine aminotransferase; AST, aspartate aminotrans ferase; TBIL, total bilirubin; DBIL, direct bilirubin; GGT, gamma-glutamyltransferase; PT, prothrombin time; PLT, platelet count; MVI, microvascular invasion; CK19, cytokeratin-19; GPC-3, glypican-3; CK7, cytokeratin-7.

Figure 2 Example of a patient with tumor cells arranged by macrotrabecular or macrotrabecular-massive appearance (cHCC-CLC-Intermediate cells subtype). (A–D). contrast‐ enhanced CT images. (E–H and J). Hematein and Eosin staining. (F and H). macrotrabecular-massive permutation (

), (G and J). vessels that encapsulate tumor clusters (VETC) pattern (

). (I and K). present outcome of CK34 in those two arrangements.

Table 2 The Results of Imaging Characteristics with Enhanced CT or MRI Between cHCC-CCA and HCC

Variable	cHCC-CCA (n = 35)	HCC (n = 35)	P value
Hypovascular component (≥50% [%])	22 (62.9%)	3 (8.6%)	0.000*
Internal arteries (%)	17 (48.6%)	16 (45.7%)	0.811
Tumor margin (smooth [%])	13 (37.1%)	23 (65.7%)	0.017*
LI-RADS category (%)			0.000*
LR-M	22 (62.9%)	5 (14.3%)
LR-TIV	3 (8.6%)	1 (2.9%)
LR-5	9 (25.7%)	28 (80%)
LR-4	1 (2.9%)	1 (2.9%)
Major imaging features
Non-rim like enhancement in AP (%)	17 (48.6%)	29 (82.9%)	0.003*
Non-peripheral “washout”in PVP or DP/TP (%)	17 (48.6%)	29 (82.9%)	0.003*
Enhancing capsule (%)	7 (20%)	16 (45.7%)	0.022*
Ancillary imaging features
Corona enhancement (%)	4 (11.7%)	3 (8.8%)	1.000
Marked diffusion restriction (%)^†	8/12 (66.7%)	6/14 (42.9%)	0.225
Mild-moderate T2 hyperintensity (%)^†	12/12 (100%)	13/14 (92.9%)	1.000
TP hypointensity (%)^†	5/12 (41.7%)	13/14 (92.9%)	0.009*
Non-enhancing capsule (%)	0	1 (2.9%)	1.000
Nodule-in-nodule (%)	0	1 (2.9%)	1.000
Mosaic architecture (%)	7 (20%)	8 (22.9%)	0.771
Fat in mass, more than adjacent liver (%)^†	2/12 (16.7%)	1/14 (7%)	0.580
Blood products in mass (%)	4(11.4%)	6(17.1%)	0.495
Targetoid mass, imaging appearance
Rim arterial phase hyperenhancement (%)	18 (51.4%)	5 (14.3%)	0.001*
Peripheral “washout” in PVP or DP/TP (%)	12 (34.3%)	4 (11.4%)	0.023*
Delayed central enhancement (%)	16 (45.7%)	1 (2.9%)	0.000*
Targetoid TP appearance (%)^†	2/12 (16.7%)	0	0.203
Targetoid diffusion restriction (%)^†	1/12 (8.3%)	0	0.462
Biliary dilatation (%)	4 (11.4%)	1 (2.9%)	0.356
Lymph node invasion (%)	3 (8.6%)	1 (2.9%)	0.614
Liver capsular retraction (%)	5 (14.3%)	2 (5.7%)	0.428

Notes: ^†Data are numbers of patients who were evaluated by MRI. Categorical variables are expressed by number and percentage. *P<0.05.

Abbreviations: cHCC‐CCA, combined hepatocellular‐ cholangiocarcinoma; HCC, hepatocellular carcinoma; CT, computed tomography; MRI, magnetic resonance imaging; LI-RADS, Liver Imaging Reporting and Data System; LR- TIV, LR tumor in vein; AP, arterial phase; PVP, portal vein phase; DP, delayed phase; TP, transitional phase.

Table 3 Univariate and Multivariate Regression Analysis of cHCC-CCA Patients

Variable	Univariable Analysis	P value	Multivariable Analysis	P value
Clinical variable
Age	1.014 (0.966–1.064)	0.567
Gender	2.077 (0.618–6.985)	0.238
Etiology
None	Reference	0.301
HBV	0.175 (0.019–1.589)	0.122
HCV	0.200 (0.011–3.661)	0.278
AFP	0.891 (0.347–2.288)	0.810
CA19-9	4.580 (1.316–15.932)	0.017*
ALT	1.003 (0.990–1.017)	0.625
AST	1.006 (0.982–1.032)	0.613
TBIL	1.018 (0.972–1.067)	0.454
DBIL	1.022 (0.958–1.091)	0.506
Albumin	1.044(0.937–1.163)	0.436
GGT	1.003 (0.996–1.010)	0.435
PT	0.700 (0.459–1.068)	0.098
PLT	1.000 (0.993–1.006)	0.885
Radiologic results
Hypovascular component ≥50%	18.051 (4.597–70.876)	0.000*	10.873 (2.549–46.391)	0.001*
Tumor size	1.633 (0.957–2.787)	0.070
Tumor margin	3.244 (1.219–8.629)	0.018*
Internal arteries	1.122 (0.439–2.868)	0.811
Major imaging features
Non-rim like enhancment in AP (%)	0.195 (0.065–0.588)	0.004*
Non-peripheral “washout”in PVP or DP/TP	0.195 (0.065–0.588)	0.004*
Enhancing capsule	0.297 (0.103–0.859)	0.025*
Ancillary imaging features
Corona enhancement	1.333 (0.275–6.457)	0.721
Non-enhancing capsule	NA	1.000
Nodule-in-nodule	NA	1.000
Mosaic architecture	0.844 (0.269–2.648)	0.771
Blood products in mass	0.624 (0.16–2.436)	0.497
Targetoid mass, imaging appearance
Rim hyperenhancement in AP	6.353 (2.0–20.179)	0.002*
Peripheral “washout” in PVP or DP/TP	4.043 (1.154–14.164)	0.029*
Delayed central enhancement	20.632 (3.517–233.071)	0.002*	14.242(1.561–129.917)	0.019*
Biliary dilatation	4.387 (0.465–41.404)	0.197
Lymph node invasion	3.187 (0.315–32.244)	0.326
Liver capsular retraction	2.750 (0.496–15.246)	0.247

Notes: Multivariate analysis with the Cox regression were used via backward LR stepwise selection. Data are reported as hazard ratios (95% CIs). *P < 0.05.

Abbreviations: cHCC‐ CCA, combined hepatocellular‐ cholangiocarcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus; AFP, alpha-fetoprotein; CA19-9, carbohydrate antigen-199; ALT, alanine aminotransferase; AST, aspartate aminotrans ferase; TBIL, total bilirubin; DBIL, direct bilirubin; GGT, gamma-glutamyltransferase; PT, prothrombin time; PLT, platelet count; AP, arterial phase; PVP, portal vein phase; DP, delayed phase; TP, transitional phase.

Table 4 Diagnostic Performance for cHCC‐ CCA

Variable	AUC	95% CIs	Accuracy (%)	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	P value
LR-M category	0.743	0.624–0.862	72.86	62.86	85.71	81.48	69.77	0.000*
Radiologic Model	0.821	0.719–0.924	80	71.43	88.57	86.21	75.61	0.000*
CA19-9+Radiologic Model	0.838	0.741–0.936	80	71.43	88.57	86.21	75.61	0.000*
Tumor size <50mm
Radiologic Model	0.866	0.746–0.986	87.76	76.19	96.43	84.38	94.12	0.000*
CA199+Radiologic Model	0.854	0.723–0.986	87.76	76.19	96.43	84.38	94.12	0.000*
Tumor size ≥50mm
Radiologic Model	0.714	0.497–0.932	61.90	64.29	57.14	75.00	44.44	0.054
CA199+Radiologic Model	0.730	0.511–0.948	66.67	71.43	57.14	76.92	50.00	0.040*
LR-4/5
Radiologic Model	0.633	0.413–0.853	79.49	30	96.55	75.00	80.00	0.273
CA199+Radiologic Model	0.717	0.508–0.927	82.05	50	93.10	71.43	84.36	0.042*
LR-M
Radiologic Model	0.841	0.686–0.996	81.48	90.90	40.00	86.96	50.00	0.000*
CA199+Radiologic Model	0.859	0.703–1.015	81.48	90.90	40.00	86.96	50.00	0.000*

Note: *P<0.05.

Abbreviations: cHCC‐ CCA, combined hepatocellular‐ cholangiocarcinoma; CA 19–9, Carbohydrate antigen-199; AUC, area under the curve; CI, confidence interval.