Review to better understand the macroscopic subtypes and histogenesis of intrahepatic cholangiocarcinoma

Table 1 Clinical study of intrahepatic cholangiocarcinoma

Ref.	n	Survival rate (%)	MST (mo)	Prognostic factor
Marubashi et al[6]	111	59.7 (3 yr)	-	IM, Hilar inv, LN
Guglielmi et al[7]	145	-	19 (LN+), 42 (LN-)	LNR > 0.25, LN
Zhu et al[8]	37	-	-	CA19-9, Low prealbmin
Dhanasekaran et al[9]	105	-	16	V
Wang et al[10]	367	-	-	CEA, CA19-9, Size, V
De Rose et al[11]	79 (MF)	-	-	Doubling time < 70 d
Sulpice et al[12]	87	-	-	BT, Maj, Size, V, IM
Ribero et al[13]	434	39.8 (5 yr)	-	LN, CA19-9, IM
Liu et al[14]	132	-	-	Por, CA19-9, Dis(-)
Uchiyama et al[15]	334	-	-	Shown in Table 2
Chen et al[16]	64	32 (3 yr)	-	LN, PN, Size
Uno et al[17]	273	-	-	Shown in Table 2
Morine et al[18]	22	-	-	Shown in Table 2
Jiang et al[19]	102	-	-	CA19-9, IM
Murakami et al[20]	44	47 (5 yr)	-	LN
Clark et al[21]	4893	8.4 (5 yr, LN+)	-	LN
		25 (5 yr, LN-)
de Jong et al[22]	449	31 (5 yr)	27	IM, V, LN
Li et al[23]	115	-	-	Cirrhosis
Chen et al[24]	320	-	-	-

MST: Median survival time; Prognostic factor: Factor for poor prognosis; IM: Multiple tumors or intrahepatic metastasis; Hilar inv: Hilar invasion; LN: Lymph node metastasis; LNR: Rate of the positive lymph node metastasis; CA19-9: Elevated serum carbohydrate antigen 19-9; CEA: Elevated serum carcinoembryonic antigen; Size: Larger tumor size; V: Vascular invasion; BT: Blood transfusion during operation; Dis: Lymph node dissection; PN: Perineural invasion.

Table 2 Clinical studies of intrahepatic cholangiocarcinoma focused on the macroscopic subtypes

Ref.	n	Findings or conclusion
Uchiyama et al[15]	334	Lymph node metastasis: MF: 16%; IG: 0%; PI and MF + PI: 60%
		Survival rate (5 yr): MF: 26%; IG: 79.3%; PI and MF + PI: 19.4%
Uno et al[17]	273	Rate of PI-type: 7.9%
		The PI-type shows significantly better survival than MF- and MF + PI-type.
Morine et al[18]	22	The PI-type shows a lower incidence of intrahepatic metastasis
		Routine lymph node dissection do not improve survival in MF-type

MF: Mass-forming type; IG: Intraductal growth type; PI: Periductal infiltrative type

Table 3 Radiologic studies of intrahepatic cholangiocarcinoma

Ref.	n	Method	Findings or conclusion
Nanashima et al[25]	42	CT	Factor for poor prognosis: case showing arterial enhancement with lower attenuation
Kim et al[26]	20	MRI	6 (30%) of the 20 cases appeared as hypervascular lesions with washout on delayed phase
Kang et al[27]	50	MRI	Percentage of relative enhancement on hepatobiliary phase was significantly higher in moderately differentiated tumors than in poorly differentiated tumors and in patients without than in those with lymph node metastasis
Xu et al[28]	40	Contrast enhanced ultrasono-graphy	MF-type (n = 32): (1) peripheral rim-like hyperenhancement (n = 19); (2) heterogenous enhancement (n = 10); and (3) homogenous hyperenhancement (n = 3)
Ariizumi et al[29]	26	FDG PET	PI-type (n = 4): heterogenous enhancement (n = 4) IG-type (n = 4): (1) homogenous hyperenhancement (n = 3); and (2) heterogenous enhancement (n = 1) FDG PET was able to predict patient outcome after radioembolization treatment

CT: Computed tomography; MRI: Magnetic resonance imaging; FDG PET: ¹⁸F-fluorodeoxy glucose positron emission tomography.

Table 4 Pathobiological studies of intrahepatic cholangiocarcinoma

Ref.	n	Method	Target	Conclusion
Gu et al[32]	85	IHC	E-cadherin	(-)por
			Beta-catenin	(-)por
			Vimentin	(-)por
Yan et al[33]	49	IHC	Smad4	(-)por, advanced stage, LN
Kamphues et al[34]	65	DNA-Cyto	DNA-index	(+)poor prognosis
Mano et al[35]	132	IHC	Roundabout-1	(-)Size, Ki67index, poor prognosis
			Slit-1	(-)PN, LN
Yin et al[36]	411	Serum	γ-glutamyl transferase	(+)V, LN, poor prognosis,
				incomplete encapsulation
Sulpice et al[37]	40	mRNA	Osteopontin	(+)poor prognosis
		(Stroma)	TGFβ2	(+)poor prognosis
			Laminin	(+)poor prognosis
Zhou et al[38]	Cell	mRNA	Notch-1	(+)EMT
	line	Western
Li et al[39]	173	IHC	CKAP4	(+)favorable prognosis
Nanashima et al[40]	38	IHC	CD44	(+)PI-type, poor prognosis
			Gli1	(+)poor prognosis
Nutthasirikul et al[41]	-	mRNA	Δ133p53/TA	(+)poor prognosis
			P53
	-	IHC	Mutantp53	(+)poor prognosis
Zhang et al[42]	33	mRNA	Capn4	(+)LN, advanced stage,
		Western		Poor prognosis
Ding et al[43]	20	IHC	Integrinα6	(+)IM, Size, V, poor prognosis
		Cell	Integrinα6	(-)decrease of metastasis
Aishima et al[44]	134	IHC	Cox-2	(+)poor prognosis, LN
			iNOS	(-) LN
Chen et al[45]	61	IHC	IMP3	(+)Por, advanced stage, V
				poor prognosis, CA19-9

IHC: Immunohistochemistry; mRNA: Real-time polymerase chain reaction; Western: Western blotting; DNA-cyto: DNA image cytometry; Cell: Functional analyses using cell lines; CKAP4: Cytoskeleton-associated protein4; iNOS: Inducible nitric oxide synthase; IMP3: Insulin-like growth factor II mRNA binding protein.

Table 5 Pathobiological studies of intrahepatic cholangiocarcinoma 2

Ref.	n	Method	Target	Conclusion
Shi et al[46]	138	IHC	DKK-1	(+)poor prognosis
				elevated sMMP9 and VEGF-C
		Cell	DKK-1	(-)decrease in cell migration and invasiveness
				(+)LN, Por, advanced stage, V
Yao et al[47]	96	IHC	Vimentin	poor prognosis
			and
			N-cadherin	(+)MF-type
Zhou et al[48]	54	IHC	HBx-protein	well differentiated tumor
				(+)well differentiated tumor, IG-type
Choi et al[49]	46	IHC	CK20	(+)favorable prognosis
			MUC6	(+)Size, LN, V, advanced stage
Jeong et al[50]	43	IHC	FABP-5	(-)decrease in cell proliferation and
		Cell	FABP-5	invasion
				(+)elevated serum CEA and CA
Tsai et al[51]	112	IHC	S100P	19-9 value, MUC2 positive
				poor prognosis
				(+)perineural invasion
	86	Sequencing	K-ras mutation	poor prognosis
			miR-200c	(+)reduction of EMT
Oishi et al[53]	-	Microarray		reduction of NCAM1 expression
			HCV core	(+)enhanced NFAT expression
Liao et al[54]	-	Cell	protein	(+)enhanced Angiotensin II receptor expression and fibrogenesis of
			Angiotensin	cancerous stroma, metastasis
Okamoto et al[55]	-	Cell	II and SDF1

DKK1: Dickkopf-related protein1; MMP: Matrix metalloproteinase; FABP-5: Fatty acid-binding protein 5; SDF1: Stromal cell derived factor 1; NCAM1: Neural cell adhesion molecule1; EMT: Epithelial mesenchymal transition; NFAT1: Nuclear factor of activated T-cells.

Table 6 Pathobiological studies of intrahepatic cholangiocarcinoma 3

Source	n	Method	Target	Conclusion
Li et al[56]	-	Tissues	miR-214	(-)increased expression of Twist(EMT
				-associated gene)
Gu et al[57]	123	IHC	IL-17cells	(+)poor prognosis
			(intratumoral)
Higashi et al[58]	63	IHC	MUC16	(+)poor prognosis
Gu et al[59]	83	IHC	E-cadherin	(-)poor prognosis
			Beta-catenin	(-)V
			EGFR	(+)Por
Wang et al[60]	77	IHC	P-70S6K	(+)Por
			4EBP1	(+)poor prognosis
Hirashita et al[61]	35	IHC	MMP-7	(+)poor prognosis
Srimunta et al[62]	55	IHC	ABCC-1	(+)poor prognosis
Morine et al[63]	35	IHC	HDAC	(+)advanced stage, LN
				poor prognosis
Wakai et al[64]	34	IHC	RRM1	(+)gemcitabine resistance
Larbcharoensub et al[65]	60	IHC	ABCG2	(-)poor prognosis, LN, Por
Lee et al[66]	101	IHC	PTEN	(+)favorable prognosis
			P-AKT1	(+)favorable prognosis
			P-MTOR	(+)favorable prognosis
Dong et al[67]	108	IHC	Beclin1	(-)LN, poor prognosis
Shinozaki et al[68]	83	IHC	Claudin-18	(+)LN, PI-type, perineural invasion
Wakai et al[69]	34	IHC	NQO1	(-)Por, poor prognosis
Aishima et al[70]	110	IHC	S100P	(+)PI-type
			S100P(nuc)	(+)LN, V
Zhou et al[71]	89	IHC	MAGE3/4	(+)larger tumor size, poor prognosis

EGFR: Epidermal growth factor receptor; P-70S6K: P70 ribosomal protein S6 kinase; 4EBP1: 4E-binding protein-1; ABCC-1: Adenosine triphosphate binding cassette C1; HDAC: Histone deacetylase; RRM1: Ribonucleotide reductase-M1; ABCG2: Adenosine 5’ triphosphate-binding cassetteG2; PTEN: Phosphatase and tensin homolog on chromosome ten; PAKT: Phosphorylated Akt; PMTOR: Phosphorylated MTOR; NQO1: Quinine oxidoredactase; MAGE: Melanoma antigen.

Table 7 Clinical studies of combined hepatocellular-cholangiocarcinoma

Source	n	Conclusion or findings
Yap et al[74]	11	Survival rate: 69.3% (3 yr)
Lee et al[75]	65	(1) The clinical characteristics of cHCC-CC are similar to those of HCC
		(2) Overall survival of cHCC-CC is similar to that of ICC
Yin et al[76]	113	(1) Findings similar to HCC: infection with hepatitis virus; presence of cirrhosis; elevated AFP levels
		(2) Findings similar to ICC: serum CA19-9 elevation; incomplete capsules; lymph node involvement
		(3) Survival rate: 41.4%(3 yr); 36.4% (5 yr)
		(4) Factors for poor prognosis: radical liver resection
Ariizumi et al[77]	44	(1) Survival rate: 24%
		(2) Median survival time: 15.4 mo
Yu et al[78]	14	(1) Clinical characteristics: hepatitis B virus infection: 13/14;
		elevated AFP levels: 11/14
		(2) Median survival time: 7.9 mo
		(3) Stem cell markers (IHC): c-Kit 71.4%; CD90: 85.7%; CD133: 92.9%; CK19: 78.6%
Park et al[79]	21	Factor for poor prognosis: serum AFP levels
Park et al[80]	43	(1) median survival time: 34 mo
		(2) Survival rate: 18.1% (5 yr)
		(3) Factors for poor prognosis: Portal vein thrombosis; distant metastasis
Zhan et al[81]	27	(1) CK-7: 86.4%; CK19: 90.9%
		(2) Survival rate: 49.4%
		(3) Factors for higher recurrence: lymph node metastasis

AFP: Alpha-fetoprotein.

Table 8 Radiologic studies of combined hepatocellular-cholangiocarcinoma

Ref.	n	Methods	Conclusion or findings
Ijichi et al[82]	3	FDG	(1) SUVmax value of three cHCC-CC cases: 9.9, 12.0, and 13
		-PET	(2) Median SUVmax value of poorly differentiated HCC: 5.7
			(1) 6/11 showed early ring enhancement with progressive enhancement in central portion.
			(2) 5/11 showed a diffuse heterogenous early enhancement.
de Campos et al[83]	11	MRI	Characteristics findings of cHCC-CC: irregular shape and strong rim enhancement during early phase; absence of target appearance on hepatobiliary-phase
Hwang et al[84]	20	MRI

cHCC-CC: Combined hepatocellular-cholangiocarcinoma; MRI: Magnetic resonance imaging; FDG-PET: ¹⁸F-fluorodeoxy glucose positron emission tomography.

Table 9 Pathobiological studies of combined hepatocellular-cholangiocarcinoma

Ref.	n	Method	Target	Conclusion
Kim et al[85]	58	IHC	YAP1	(+): transition zone, poor prognosis
			EpiCAM	(-)favorable prognosis
			CK19	(-)favorable prognosis
Ikeda et al[86]	36	IHC	DLK1	(+)poor prognosis
Akiba et al[87]	54	IHC	CD56	(+): components apart from HCC
			c-Kit	(+): components apart from HCC
			EpiCAM	(+): components apart from HCC
			CD133	(+): intermediate type or cholangiolocellular type
			Vimentin	(+): intermediate type or cholangiolocellular type
Coulouarn et al[88]	152	Microarray	-	(1) TGFbeta and beta-catenin are identified as the two major signals in the progression of cHCC-CC/
				(2) cHCC-CC shares the characteristics of poorly differentiated HCC.
				(+)poor prognosis
				Both HCC and CC components of most
				Of the cHCC-CC express both AFP and
Cai et al[89]	80	IHC	PCNA	CK19
Itoyama et al[90]	20	IHC	AFP and
			CK19

cHCC-CC: Combined hepatocellular-cholangiocarcinoma; YAP1: Yes-associated protein 1; EpiCAM: Epithelial cell adhesion molecule; DLK1: Delta-like 1 homolog; PCNA: Proliferating cell nuclear antigen index in nontumor ductular reaction.