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Introduction
Background
Cholangiocarcinoma (CCA) is an adenocarcinoma characterized by differentiation of
the bile duct epithelium. Based on its anatomical location, CCA is classified
into intrahepatic CCA (iCCA), perihilar CCA (pCCA), and distal CCA (dCCA) [1,2].
CCAs located more peripherally than the second confluence of the bile ducts are
classified as iCCA, those situated between the second confluence and the cystic
duct insertion site on the common bile duct are categorized as pCCA, and those
found distal to the cystic duct insertion are classified as dCCA [3]. iCCAs account for 10% to 20% of all
CCAs, while pCCAs (50% to 60%) and dCCAs (20% to 30%) are more common [3]. However, while the rates of pCCA and
dCCA are decreasing, the age-standardized incidence of iCCA has been rising
globally over the past few decades, necessitating closer attention [3]. iCCA is the second most common primary
liver cancer after hepatocellular carcinoma (HCC) and has a worse prognosis than
HCC [4]. Recently, our understanding of
iCCA has improved, and it is now recognized as a heterogeneous tumor with
diverse etiology, clinical presentation, pathology, and genetic characteristics.
The clinical significance of this heterogeneity is being increasingly
recognized.
iCCA often presents as a mass with variable shapes, including lobulated or
irregular contours, and may be associated with bile duct dilatation, vascular
encasement, and regional lymph node metastasis [5]. The enhancement patterns observed on dynamic CT or MRI are
diverse; typically, peripheral enhancement is evident in the arterial phase,
followed by centripetal enhancement in later phases [6,7]. On MRI, most
iCCAs exhibit high signal intensity on T2-weighted images relative to the
surrounding liver parenchyma, display diffusion restriction on
diffusion-weighted images, and appear hypointense in the hepatobiliary phase
when gadoxetic acid is used as a contrast medium [6–8]. The imaging
characteristics of iCCA are heterogeneous, reflecting the recently recognized
diversity of the disease. Accumulating evidence suggests that these imaging
features can be clinically applied to predict prognosis and guide treatment
decisions [9,10].
Ethics statement
As this study is based on a review of the literature, neither institutional review
board approval nor informed consent was required.
Histopathologic subclassification of intrahepatic cholangiocarcinoma
In the fifth edition of the World Health Organization classification, updated in
2019, a new histological subclassification of iCCA was introduced, delineating small
duct (SD-iCCA) and large duct (LD-iCCA) types [11,12]. SD-iCCA and LD-iCCA are
distinct not only in their histopathological morphology but also in their etiology,
tumor location, gross morphology, histopathological characteristics such as
invasiveness and vascularity, molecular features, and prognosis (Table 1).
Table 1.
Comparison of characteristics between small duct and large duct iCCA
iCCA, intrahepatic cholangiocarcinoma; PSC, primary sclerosing cholangitis; BilIN, biliary intraepithelial neoplasia; IPNB, intraductal papillary neoplasm of the bile duct; NCAM, neural cell adhesion molecule; N-cadherin, neural cadherin; IDH, isocitrate dehydrogenase; FGFR2, fibroblast growth factor receptor 2; KRAS, Kirsten rat sarcoma viral oncogene homolog; MVD, microvessel density.
SD-iCCA typically arises in the small bile ducts within the peripheral liver, often
in the context of chronic hepatitis and cirrhosis. It is characterized by an
exclusively mass-forming (MF) gross morphology [13]. Histologically, SD-iCCA consists of cuboidal or low columnar cells
arranged in a tubular or cord-like glandular pattern. Compared to LD-iCCA, SD-iCCA
is less frequently associated with aggressive pathological features, such as
perineural invasion, vascular invasion, and lymph node metastasis [14]. It also tends to have a higher
microvascular density (MVD) and exhibits necrosis less frequently. Overall, SD-iCCA
has a more favorable prognosis than LD-iCCA [15,16].
LD-iCCA typically originates in the large bile ducts near the hilum and is often
associated with underlying chronic bile duct diseases such as hepatolithiasis, liver
fluke infestation, or primary sclerosing cholangitis [13]. LD-iCCA frequently arises from a multistep carcinogenesis
process, with well-known precursor lesions including biliary intraepithelial
neoplasia and intraductal papillary neoplasm of the bile duct [17]. It usually develops from either periductal-infiltrating or
intraductal-growing tumors of the large bile duct [14]. These tumors can further evolve into the MF type or present as a
hybrid of the MF and either the periductal-infiltrating or the intraductal-growing
type [18]. Compared to the SD-iCCA, LD-iCCA
more frequently exhibits perineural invasion, vascular invasion, and lymph node
metastasis; it also displays lower MVD and more frequent necrosis [14,19].
LD-iCCA has a poorer prognosis than SD-iCCA due to its high invasiveness, which
leads to frequent recurrence after curative surgical resection and resistance to
chemotherapy [20,21].
Utilizing imaging findings to predict prognosis in intrahepatic cholangiocarcinoma
Imaging assessment of the American Joint Committee on Cancer, Eighth Edition, tumor-node-metastasis staging system
The prognosis of iCCA in clinical settings is generally stratified using the
eighth edition of the American Joint Committee on Cancer (AJCC) staging system.
This system incorporates the tumor, node, metastasis (TNM) classification [22] and was developed and validated through
pathological assessment of tumor involvement [22–25]. In iCCA
staging, the T category is defined by several factors, including the size of the
tumor (with a threshold of 5 cm), the number of tumors present, vascular
invasion, visceral peritoneal perforation, and invasion of extrahepatic organs.
The N category signifies the presence of regional lymph node metastasis, while
the M category indicates distant metastasis. Although TNM staging should be
definitively determined through pathological examination of resectable tumors,
imaging-based staging is commonly employed to predict prognosis and guide
treatment decisions for tumors prior to surgical resection or those deemed
unresectable.
The eighth edition of the AJCC provides brief guidance on the clinical TNM
classification for iCCA, noting that both contrast-enhanced CT and MRI are
valuable for detecting tumors larger than 2 cm and assessing vascular
involvement. Additionally, it indicates that magnetic resonance
cholangiopancreatography can offer additional insights into the extent of
disease. However, recent clinical practice guidelines from the European
Association for the Study of the Liver and the International Liver Cancer
Association (EASL-ILCA) recommend MRI over CT for the staging of iCCA [2]. This guidance is supported by a
multicenter retrospective study that directly compared these modalities and
revealed the superiority of MRI in staging MF-iCCAs, especially for tumors
classified as T1b, T2, and T3/T4. Specifically, MRI displayed better performance
in predicting T category components, such as tumor multiplicity, vascular
invasion, and visceral peritoneal invasion [26].
Tumor size and multiplicity
The eighth edition AJCC staging system for iCCA categorizes solitary tumors
as T1a or T1b, depending on whether the tumor is larger or smaller than 5
cm. This classification is underpinned by multiple studies demonstrating
that tumors exceeding 5 cm are linked to comparatively poor survival
outcomes and a high likelihood of recurrence [27–29].
Recent research has confirmed the reliability of preoperative imaging for
accurately estimating iCCA tumor size, revealing a median difference of less
than 0.5 cm between pathological and radiological measurements [30]. Furthermore, a study comparing the
effectiveness of CT and MRI for determining iCCA tumor size reported no
significant difference between these modalities [26].
Tumor multiplicity is another key determinant for the T category in the AJCC
staging system, with its presence categorizing a tumor as T2. Multiplicity
is defined as the presence of satellitosis, multifocal tumors, or
intrahepatic metastasis [22]. Studies
have demonstrated that tumor multiplicity is linked to poorer overall
survival and a higher risk of tumor recurrence after resection [31,32]. As previously noted, a recent study showed MRI to be
superior to CT in the imaging assessment of tumor multiplicity [26].
In both CT and MRI dynamic imaging studies, the assessment of tumor size and
the detection of satellite nodules in iCCA typically involve the use of the
portal venous phase [26,33]. Regarding MRI, hepatobiliary phase
and diffusion-weighted imaging are also useful, particularly for detecting
small lesions [34,35].
Vascular invasion
Vascular invasion, which includes both macrovascular invasion and
microvascular invasion (MiVI) observed on histopathologic examination, is a
major prognostic factor for iCCA. Specifically, it assigns a stage of T2 in
the eighth edition AJCC system [22].
Research indicates that MiVI in iCCA is significantly linked to poor overall
survival. Additionally, macrovascular invasion has been associated with
comparatively low overall and disease-free survival [36,37].
The challenge of clinical staging arises from the inability to directly
observe MiVI using CT or MRI. To address this issue, recent research has
focused on identifying imaging characteristics that can predict the presence
of MiVI in iCCA. Studies have found that MiVI is more commonly associated
with larger tumors, lobulated or irregular tumor morphology, thin-rim
enhancement during the arterial phase, penetration of the hepatic artery
within the tumor, bile duct dilation, and a high apparent diffusion
coefficient (ADC) [38–40].
Lymph node metastasis
Lymph node metastasis is widely recognized as a strong prognostic factor for
iCCA [31,41]. The conventional criteria for detecting lymph node
metastasis on CT and MRI generally involve a lymph node size threshold of 1
cm in short-axis diameter, along with imaging characteristics such as round
shape, irregular margins, and internal necrosis [42]. Recent studies have demonstrated that the
inclusion of tumor imaging factors—such as arterial phase
hypoenhancement, tumor multiplicity, bile duct involvement, periductal
infiltrating growth pattern, and a primary tumor located in the left
lobe—combined with serum tumor markers like elevated carcinoembryonic
antigen and carbohydrate antigen 19-9 (CA19-9) levels, can improve the
accuracy of lymph node metastasis detection in iCCA [43–46].
However, the diagnostic accuracy of CT and MRI for detecting lymph node
metastases is generally considered to be inadequate. The most recent
EASL-ILCA guidelines advise the routine use of 18-fludeoxyglucose positron
emission tomography-CT (18F-FDG PET-CT) for patients with
apparently resectable iCCA to achieve precise clinical nodal staging [2]. This recommendation stems from a
recent meta-analysis, which revealed that MRI has a sensitivity of 64% and a
specificity of 69% for identifying lymph node metastases. In contrast,
18F-FDG PET-CT demonstrated a sensitivity of 52% but a
notably higher specificity of 92% [47].
Radiological prognosis prediction
Subclassification of intrahepatic cholangiocarcinoma
Subclassifying iCCA based on radiological findings can be useful for
predicting prognosis, as LD-iCCA is associated with a poorer prognosis than
SD-iCCA. Imaging can be employed to assess the differences in gross
morphology between these types of iCCA. SD-iCCA typically exhibits a MF
appearance with a round or lobulated shape (Figs. 1, 2) [48]. In contrast, LD-iCCA often
displays irregular contours alongside a round or lobulated shape, frequent
bile duct involvement that is readily apparent on T2-weighted MRI, and
vascular encasement (Fig. 3) [9,10,48]. Recent studies
indicate that features such as infiltrative contours, adjacent bile duct
dilatation, the absence of arterial phase hyperenhancement, and vascular
invasion are associated with LD-iCCA and are correlated with poorer
disease-free and overall survival [48,49].
Fig. 1.
A 34-year-old female patient with liver cirrhosis and small duct-type intrahepatic cholangiocarcinoma (iCCA). Gadoxetic acid-enhanced MRI: (A) pre-contrast T1-weighted, (B) arterial phase, (C) portal phase, (D) transitional phase, (E) hepatobiliary phase, (F) T2-weighted, and (G) diffusion-weighted (b=800 s/mm2) images and (H) apparent diffusion coefficient map. Staining: (I) hematoxylin-eosin, (J) C-reactive protein (CRP) immunohistochemical, and (K) mucicarmine staining (I–K, original magnification ×200). The gadoxetic acid-enhanced MRI reveals a 1.5-cm round mass in the subcapsular area of the right liver. The mass exhibits hyperenhancement in the arterial phase (B), does not show washout in the portal phase (C), and appears hypointense in the hepatobiliary phase (E). Pathological examination confirmed the lesion as a small duct iCCA with positive CRP expression (J) and the absence of mucin under mucicarmine staining (K).
Fig. 2.
A 51-year-old female patient with small duct-type intrahepatic cholangiocarcinoma (iCCA). Gadobutrol-enhanced MRI: (A) pre-contrast T1-weighted, (B) arterial phase, (C) portal phase, (D) equilibrium phase, (E) 15-minute delayed phase, (F) T2-weighted, and (G) diffusion-weighted (b=800 s/mm2) images and (H) apparent diffusion coefficient (ADC) map. Staining: (I) hematoxylin-eosin, (J) C-reactive protein (CRP) immunohistochemical, (K) Alcian blue/periodic acid-Schiff (AB/PAS), and (L) S100 calcium-binding protein P (S100P) immunohistochemical staining (I–L, original magnification ×200). The mass exhibits rim hyperenhancement in the arterial phase (B) and a progressive centripetal pattern of contrast filling in the portal (C), equilibrium (D), and delayed (F) phases. It also displays moderate hyperintensity on the T2-weighted image (F), and restriction on both the diffusion-weighted image and the ADC map (G,H). No significant bile duct dilatation is evident in the peritumoral area. The patient underwent right lobectomy, and a diagnosis of small duct iCCA was confirmed through immunohistochemical and special staining techniques. Specifically, on pathologic examination, the lesion displayed positive CRP expression (J), absence of mucin on AB/PAS staining (K), and negative staining for S100P expression (L).
Fig. 3.
A 52-year-old male patient with large duct-type intrahepatic cholangiocarcinoma (iCCA). Gadoxetic acid-enhanced MRI: (A) pre-contrast T1-weighted, (B) arterial phase, (C) portal phase, (D) transitional phase, (E) hepatobiliary phase, (F) T2-weighted, and (G) diffusion-weighted (b=800 s/mm2) images and (H) apparent diffusion coefficient (ADC) map. Staining: (I) hematoxylin-eosin, (J) mucicarmine, and (K) S100 calcium-binding protein P (S100P) immunohistochemical staining (I–K, original magnification ×200). A well-defined 3.2-cm mass is evident in segment 4 of the liver. The mass exhibits diffuse hypovascularity in the arterial phase (B); hypointensity in the portal (C), transitional (D), and hepatobiliary phases (E); adjacent bile duct dilatation on the T2-weighted image (F); and restricted diffusion on both the diffusion-weighted image and the ADC map (G,H). The patient underwent percutaneous biopsy, and a diagnosis of large duct iCCA was confirmed through immunohistochemical and special staining techniques. Specifically, the tumor displayed positive expression of both mucin (J) and S100P (K).
The imaging findings of the two types of iCCA closely align with their
pathogenesis and associated liver or bile duct diseases. SD-iCCA is
frequently accompanied by chronic hepatitis or cirrhosis, whereas LD-iCCA is
commonly associated with chronic bile duct diseases such as primary
sclerosing cholangitis, hepatolithiasis, or Clonorchis
sinensis infection [50–53].
Enhancement pattern of the tumor
The arterial enhancement pattern of iCCA is recognized as a key imaging-based
prognostic marker. Studies have shown that iCCA with arterial phase
hyperenhancement is associated with less invasive histopathological features
and better overall survival compared to iCCA with either diffuse
hypoenhancement or rim enhancement during the arterial phase (Fig. 1) [54–56].
Radiopathologic correlation studies have additionally established that MVD
is linked to arterial enhancement patterns. iCCA with low MVD typically
displays low arterial phase enhancement on imaging; furthermore, low MVD is
associated with a poor prognosis, along with aggressive pathological
features such as tumor multiplicity, MiVI, lymph node metastasis, and low
infiltration of CD8+ tumor-infiltrating lymphocytes [57,58].
Moreover, the enhancement pattern of iCCA is suspected to be associated with
its subclassification. SD-iCCA often exhibits arterial hyperenhancement,
resembling that seen in HCC or combined hepatocellular-CCA [59]. The arterial enhancement patterns
in LD-iCCA are more variable, ranging from diffuse hyperenhancement to rim
hyperenhancement and diffuse hypoenhancement [48].
Intratumoral fibrous stroma
Most iCCAs exhibit some degree of fibrous stroma. When scirrhous fibrous
stroma comprises more than 70% of the tumor area, the iCCA is classified as
scirrhous. Scirrhous iCCA is linked to a higher incidence of lymphatic and
perineural invasion and is associated with significantly worse survival
outcomes compared to non-scirrhous iCCA [60].
Intratumoral fibrosis can be assessed using dynamic CT or MRI.
Radiopathologic correlation studies have demonstrated that regions of
delayed enhancement are indicative of contrast retention within the fibrous
stroma of the tumor [61–63]. Furthermore, the degree of delayed
enhancement has been recognized as a prognostic marker for poor outcomes in
patients with MF-iCCA. Specifically, iCCAs that exhibit delayed enhancement
in more than two-thirds of the tumor on dynamic CT are associated with
scirrhous iCCA, a higher incidence of perineural invasion, and relatively
low overall survival [64].
Similarly, on gadoxetic acid-enhanced MRI, central intratumoral enhancement
observed during the hepatobiliary phase reflects the presence of fibrous
stroma within an iCCA lesion (Fig. 4)
[65,66]. During this phase, iCCAs containing fibrous stroma
exhibit an ill-defined hyperintense region set against a peripheral
hypointense area. This pattern is often described as the
“EOB-cloud,” a term derived from the chemical name of
gadoxetic acid, gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid
(Gd-EOB-DTPA) [66,67]. This cloud-like appearance results
from the extracellular accumulation of contrast in the central fibrous
stroma, while the periphery of the tumor typically contains a higher
proportion of tumor tissue and less fibrosis. Notably, MF-iCCAs in which
more than 50% of the area appears hyperintense or isointense during the
hepatobiliary phase tend to exhibit comparatively poor disease-free and
overall survival [68].
Fig. 4.
A 63-year-old male patient with intrahepatic cholangiocarcinoma (iCCA) exhibiting a dense fibrous stroma. Gadoxetic acid-enhanced MRI: (A) pre-contrast T1-weighted, (B) arterial phase, (C) portal phase, (D) transitional phase, (E) hepatobiliary phase, (F) T2-weighted, and (G) diffusion-weighted (b=800 s/mm2) images and (H) apparent diffusion coefficient map. (I) Scan view image of hematoxylin-eosin staining. MRI revealed an approximately 4.5-cm lobulated mass in the right posterior liver. The mass exhibited thin-rim hyperenhancement in the arterial phase (B), peripheral washout with progressive central enhancement in the portal (C) and transitional (D) phases, and an “EOB-cloud” appearance in the hepatobiliary phase (E), as well as targetoid diffusion restriction (G,H). The patient underwent extended right posterior sectionectomy, and the diagnosis of iCCA was confirmed. The pathology specimen (I) displayed a dense fibrotic area, corresponding to the “EOB-cloud area” observed on MRI.
Imaging-based prognosis prediction model for intrahepatic cholangiocarcinoma
Recent research has progressed from correlating imaging findings with
histopathologic characteristics associated with prognosis to creating models
that directly predict prognosis from imaging findings. These imaging-based
prognostic models can offer insights into patient outcomes before treatment is
initiated, potentially informing critical decisions about therapeutic
strategies.
A multicenter study proposed a preoperative prognostic model for resectable iCCA
that includes serum CA19-9 levels and three MRI findings: tumor multiplicity,
lymph node metastasis, and bile duct invasion [69]. In predicting overall survival, this imaging-based model
demonstrated comparable discriminatory performance to traditional pathologic
staging systems, such as the eighth edition AJCC TNM system, the MEGNA score,
and Nathan staging [69–71]. Another recent study introduced a more
sophisticated prognostic model for resectable iCCA, combining two serum markers
(CA19-9 >300 IU/mL and albumin ≤40 g/L) and six imaging findings
[72]. This model outperformed
pathologic staging systems, including the eighth edition AJCC and the MEGNA
score, in predicting disease-specific and disease-free survival [72].
Imaging-based models have also been reported for predicting the prognosis of
unresectable iCCA. The Fudan score, originally developed from a cohort of
patients with resectable iCCA, has been shown to be effective for prognostic
prediction in unresectable iCCA as well [73]. This score includes five variables: tumor diameter, the number
of intrahepatic tumors, the type of tumor boundary, serum alkaline phosphatase
levels, and CA19-9 levels. A recent study proposed a modified scoring system for
unresectable iCCA by incorporating an additional unfavorable prognostic
factor—high ADC—which improved the model’s performance in
predicting survival [74].
Utilizing imaging findings for treatment decision-making in intrahepatic cholangiocarcinoma
Imaging is vital in the treatment decision-making process for iCCA, as it aids not
only in assessing resectability but also in determining the need for lymphadenectomy
during hepatic resection, deciding whether to administer neoadjuvant therapy, and
selecting targeted therapies.
Lymphadenectomy
Lymphadenectomy plays a crucial role in accurate staging and may reduce the risk
of recurrence; however, its impact on survival remains unclear. Although the
practice of lymph node dissection in patients with clinically positive lymph
nodes (cN+) has gained broader acceptance, the routine dissection of lymph nodes
in patients who lack clear evidence of lymph node metastases (clinically
negative lymph nodes, cN–) remains a topic of ongoing debate [75,76].
The AJCC staging system, EASL-ILCA guidelines, and National Comprehensive Cancer
Network (NCCN) clinical practice guidelines all endorse the routine dissection
of lymph nodes. The AJCC and EASL-ILCA guidelines specifically recommend the
removal of a minimum of six lymph nodes to ensure thorough nodal staging. In
comparison, the NCCN guidelines simply advises regional lymphadenectomy of the
porta hepatis [2,22,77]. Conversely,
Japanese guidelines do not provide a specific recommendation concerning routine
lymph node dissection [78].
In clinical practice, lymph node dissection is performed in about half of
patients, largely based on the surgeon’s discretion [79,80]. When deciding whether to perform lymph node dissection, imaging
findings play a key role. One study revealed that a risk score combining serum
carcinoembryonic antigen level (≥7 ng/mL), lymph nodes deemed suspicious
on MRI, and MRI evidence of bile duct invasion was significantly correlated with
the presence of pathological lymph node metastasis (Fig. 5) [46].
Moreover, among patients who had a high risk score but did not undergo lymph
node dissection, the researchers observed a higher likelihood of nodal
recurrence within 3 months after surgery [46]. Imaging results can therefore be instrumental in stratifying
the risk of lymph node metastasis, thus guiding the decision of whether to
perform lymph node dissection in patients at high risk.
Fig. 5.
A 64-year-old female patient with intrahepatic cholangiocarcinoma (iCCA) and lymph node metastasis. Gadoxetic acid-enhanced MRI, comprising (A) pre-contrast T1-weighted, (B) arterial phase, (C) portal phase, (D) hepatobiliary phase, (E) diffusion-weighted (b=800 s/mm2), and (F) T2-weighted images, reveals a 3.5-cm infiltrative, poorly enhancing mass in the left lobe, with adjacent bile duct dilatation. Additionally, the (G) portal phase image and (H) 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-CT display an enlarged lymph node with increased 18F-FDG uptake situated adjacent to the common hepatic artery (white arrows). The patient underwent left hepatic lobectomy with lymph node dissection, and pathological examination confirmed the diagnosis of iCCA with regional lymph node metastases.
Neoadjuvant therapy
Currently, the literature includes no prospective evidence specifically
supporting neoadjuvant therapy for iCCA, and no randomized studies have directly
compared neoadjuvant chemotherapy followed by surgery with surgery alone.
However, two retrospective studies, both analyzing data from the US National
Cancer Database, yielded notable findings.
One study demonstrated that patients with a higher clinical T stage or clinical
lymph node metastasis who received neoadjuvant therapy had better survival
outcomes than those who underwent upfront surgery [81]. Similarly, another study found that although no
survival benefit was observed in a propensity score-matched analysis across all
stages of iCCA, neoadjuvant therapy did confer a survival advantage in patients
with more advanced disease (stages II-III) [82].
As a result, guidelines vary in their recommendations concerning neoadjuvant
therapy for iCCA. The EASL-ILCA guideline states that neoadjuvant systemic
chemotherapy can be considered for patients with surgically challenging yet
resectable disease, especially when an R1 resection is anticipated [2]. In contrast, neither the NCCN nor the
Japanese guidelines provide specific recommendations for neoadjuvant therapy in
the context of iCCA [77,78]. Well-designed prospective trials are
necessary to further evaluate the role of neoadjuvant treatment in this
context.
Collectively, neoadjuvant therapy has been demonstrated to confer a survival
benefit in cases with a high T stage, suspected nodal metastasis, or a high
likelihood of positive resection margins. Considering that imaging-based
prognostic models are highly effective at predicting postoperative outcomes, the
use of imaging to identify high-risk patients who might benefit from neoadjuvant
therapy could represent a viable strategy [72].
Molecular profiling for targeted therapy
In recent years, targeted therapy has become increasingly important in the
treatment of iCCA [83]. The standard
first-line treatment consists of a combination of gemcitabine, cisplatin, and
durvalumab. However, targeted therapies are emerging as a viable second-line
option for patients with specific genetic mutations [2,77]. These
therapies require molecular profiling, often performed through next-generation
sequencing, which can be expensive. Molecular profiling is typically recommended
for patients with advanced-stage disease who need systemic therapy and for
early-stage patients at high risk of recurrence. Imaging findings can be
instrumental in identifying and stratifying these high-risk patients.
Currently, approved targeted therapies are available for genetic factors
including isocitrate dehydrogenase 1 (IDH1) mutation,
fibroblast growth factor receptor 2 (FGFR2) fusion,
BRAF V600E mutation, microsatellite instability-high and
mismatch repair-deficient cancers, and epidermal growth factor receptor 2
(HER2) overexpression [84–88]. Among these,
IDH1 mutation and FGFR2 fusion are
particularly impactful due to their comparatively high incidence [77]. These mutations are predominantly
observed in SD-iCCA [18]. Studies have
shown that iCCA with IDH1/2 mutations often presents with
pronounced arterial phase enhancement on imaging, a feature commonly associated
with SD-iCCA [89]. Given the higher
prevalence of targetable mutations such as IDH1 and
FGFR2 within the small duct type, molecular profiling may
be particularly promising when imaging findings suggest the presence of SD-iCCA
(Fig. 6). However, limited research is
available to support this recommendation.
Fig. 6.
A 42-year-old female patient with intrahepatic cholangiocarcinoma (iCCA) harboring an isocitrate dehydrogenase 1 (IDH1) mutation. Gadoxetic acid-enhanced MRI, comprising (A) pre-contrast T1-weighted, (B) arterial phase, (C) portal phase, (D) transitional phase, (E) hepatobiliary phase, (F) T2-weighted, and (G) diffusion-weighted (b=800 s/mm2) images, as well as (H) apparent diffusion coefficient map, reveal a 4.5-cm well-defined mass in the right liver dome. The mass exhibits rim hyperenhancement in the arterial phase (B), a targetoid appearance in the transitional and hepatobiliary phases (D,E), hyperintensity on the T2-weighted image (F), and diffusion restriction (G,H). The lesion is situated peripherally in the liver without evidence of adjacent biliary dilatation. The patient underwent central lobectomy, and iCCA was confirmed. Next-generation sequencing identified an IDH1 missense mutation.
Conclusion
iCCA represents a serious and escalating global health concern, with a rising
incidence and persistently poor prognosis. However, advancements in pathology and
radiology have provided new insights into the disease. The histological
subclassification into SD-iCCA and LD-iCCA offers a valuable framework for
understanding the heterogeneity of iCCA and improving prognosis prediction.
Radiological studies that focus on various imaging findings, such as tumor size,
multiplicity, enhancement patterns, the presence of intratumoral fibrous stroma, and
suspicious lymph nodes, have demonstrated high utility in the pre-treatment
assessment of patients.
Importantly, imaging-based prognostic models for resectable iCCA have demonstrated
predictive accuracy comparable to that of traditional pathological staging systems.
Beyond predicting prognosis, imaging also offers critical insights that may inform
decisions about lymphadenectomy and neoadjuvant therapy. Furthermore, radiological
findings indicative of SD-iCCA could assist in identifying patients likely to harbor
clinically relevant mutations, such as IDH1 mutatios and
FGFR2 fusions.
These imaging-based approaches are essential for improving prognosis and tailoring
treatment strategies for patients with iCCA, thereby advancing personalized medicine
in this area. Nevertheless, to increase the utilization of imaging findings in
predicting prognosis and informing treatment decisions, higher-level evidence from
international multicenter prospective studies is necessary.
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