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Combined hepatocholangiocarcinoma (cHCC-CCA) is an uncommon primary liver lesion in which aspects of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are intimately and unequivocally expressed. Its origin is still a topic of debate, given its heterogeneity, molecular profile, gene mutations, and also the complexities of the microenvironment in which it develops and the pathways that are triggered in the liver in relation to the phenomena of liver damage. Diagnosis and treatment are still a challenge, given the rarity of the disease and the complex heterogeneity of the tumor itself. Resective surgery remains the treatment of choice, but there is no strong recommendation regarding lymphadenectomy, with liver transplant still being controversial. There is still a lack of standards of care with regard to systemic therapy, but there are some promising findings on the efficacy of immune checkpoint inhibitors.
General Surgery Unit Area Medica Department, ASUFC University of Udine San Daniele del Friuli, Udine, Italy
Vittorio Bresadola
General Surgery Unit Area Medica Department, ASUFC University of Udine San Daniele del Friuli, Udine, Italy
Serena Pullini
Department of Radiology, ASUFC University of Udine, Udine, Italy
Serena Battista
Pathology Department, ASUFC University of Udine, Udine, Italy
Aron Zompicchiatti
Area Medica Department General Surgery, ASUFC University Hospital of Udine, Udine, Italy
Alessandro Uzzau
Area Medica Department General Surgery, ASUFC University Hospital of Udine, Udine, Italy
*Address all correspondence to: anna.rossetto@asufc.sanita.fvg.it
1. Introduction
Combined hepatocholangiocarcinoma carcinoma (cHCC-CCA; hepatocellular carcinoma [HCC] and cholangiocarcinoma [CCA]) is an uncommon primary liver tumor. The 2019 WHO definition of cHCC-CCA is a primary liver carcinoma with evident components of both hepatocytic and cholangiocytic differentiation [1].
Its incidence varies from 0.4% to 14.2% of all liver cancers [2, 3]. The wide range of incidence percentages is likely to be attributable to multiple aspects; on one hand, the succession of different classifications has, at times, been included in the definition of cHCC-CCA tumors that are no longer considered.
On the contrary, since liver biopsy is not mandatory before locoregional treatments, histological confirmation is not available either before or after treatment in a very large number of patients. This certainly caused the unawareness of cases of cHCC-CCA with predominant radiological features more suggestive of another liver tumor, but since it carries a worse prognosis overall than HCC and CCA alone, the need for pretreatment diagnosis is mandatory. However, this is still a challenge given the rarity and the heterogeneous aspects of the pathology, but it is essential to initiate the patient to the most correct treatment [4].
2. Origin and classification
The first report about cHCC-CCA dates back to the early 1900s, with Wells, who had already proposed that the origin was to be found in cells that came from the same embryology and subsequently differentiated in a hepatocellular and cholangiocellular sense [5]. Recent studies suggest that CCA can originate from hepatic progenitor cells [6].
2.1 Origin
Defining the precise nature of the neoplasm in a rare tumor with aggressive behavior and without specific consensus on therapeutic guidelines is of fundamental importance for the most correct treatment.
Some argued that cHCC-CCA derives from hepatocytes by virtue of the molecular profile of this neoplasm, which is extremely similar to HCC while very dissimilar from CCA. Studies on mutational analysis of cHCC-CCA have shown a profile more similar to HCC due to the presence of similar alterations (TERT, TP53 cell cycle genes, Wnt pathway genes, and chromatin regulators), while some of the most frequent CCA gene mutations are absent in cHCC-CCA (IDH1, IDH2, FGFR2 and BAP1) [7–9].
Others suggested instead that cHCC-CCA and CCA share the same origin, in opposition to HCC, based on studies of the genetic alterations showing loss of heterozygosity at 3p and 14q, common in both CCA and cHCC-CCA but not in HCC, suggesting a common pathway of alterations and consequently a similar pathogenesis for cHCC-CCA and CCA [10].
If it is accepted that HCC derives from mature hepatocytes and CCA derives from cholangiocytes, recent issues regarding liver parenchymal cells highlight plasticity mechanisms, leading to the consideration of primary liver tumors as subtypes of a continuous spectrum of diseases.
Mature hepatocytes can give rise to primary liver cancer through several routes: direct degeneration into HCC by a mature hepatocyte that has sustained genomic sequencing damage, through the phenomenon of de-differentiation of a mature hepatocyte into a progenitor cell that, in turn, may give rise to HCC, or through trans-differentiation in a cholangiocytic sense, leading to the occurrence of CCA.
Mature cholangiocyte, on the contrary, does not have the same plasticity as hepatocyte and can only give rise to CCA [11, 12].
During acute reduction of liver mass, hepatocyte turnover is greatly accelerated, giving rise to the phenomenon that occurs after hepatectomy and is characterized by rapid restoration; during chronic liver damage, the regenerative capacity of hepatocytes is reduced. Under these circumstances, epithelial cells with the capacity for bivalent differentiation in both hepatocellular and cholangiocytic directions are activated through the phenomenon of ductular reaction.
Some studies, focused on the hepatic background on which the neoplasm originates, have also highlighted a determined effect in the presence or absence of liver disease on the origin of the neoplasm. Particularly, in the presence of hepatitis infection, the similarity between HCC and primary hepatic tumors with a biliary phenotype is such as to suggest a common origin from pluripotent cells. In contrast, in seronegative cases, tumors with a biliary phenotype could have a different origin, that is, cholangiocytic origin [13].
Some driver mutations, such as hotspot mutations in KRAS, IDH1/2, and the TERT promoter, were different in the various cancer types, depending on the presence or absence of a hepatitis background [13].
A recent paper by Rosenberg et al. [11] attributes, in a very intriguing way, the origin of cHCC-CCA to pluripotent cells of the hepatobiliary junction that would be activated in a senescent microenvironment through the interleukin 6 pathway [9], in a completely different manner with respect to HCC, which is triggered after acute stress.
Interleukin-6 (IL-6) is related to senescence, and when acute liver damage occurs, it behaves as a protumor factor, causing an increase in senescence, showing a senescence-associated secretory phenotype (SASP), and promoting hepatocyte proliferation in the direction of HCC.
In the context of chronic damage, IL-6 seems to trigger a cascade of events in the opposite direction, suppressing hepatocyte division and hepatocarcinogenesis, but activating retro-dedifferentiation. This pathway, through dedifferentiation to progenitor cells and subsequent malignant transformation, could lead to cHCC-CCA [14–16].
Modulation of cell senescence expression by senolytic agents inducing senescent cell apoptosis has demonstrated a protective action toward the differentiation of cHCC-CCA or the reduction of tumor mass of HCC-CCA already present, as shown in studies on mice [11, 17, 18].
Some studies have shown that the differentiation toward hepatocellular rather than in the cholangiocellular direction could be determined by microenvironment modifications and by the only partial achievement of necrosis by means of locoregional ablation techniques.
Others have demonstrated the presence of mixed phenotypic aspects, suggestive of differentiation in the cholangiocytic sense, in the residual vital portion, as well as a sarcomatous “drift” in some cases after trans-arterial chemo embolization (TACE) treatment [19–21] or other locoregional treatments [21–23].
When post-TACE incomplete necrosis occurred, a phenotype that mimics CCA with expression of markers of biliary progenitors (CK7, CK19), as well as the presence of markers that are suggestive of CK133 progenitor cells, is described.
TACE could induce a more aggressive form of HCC characterized by a biliary phenotype [21]. The limitation of these studies is that there is no biopsy before treatment, but only one on the operative piece after hepatectomy during transplantation for HCC downstaged with TACE. However, these aspects and the expression of typical markers were absent in the patients who did not undergo treatment with TACE [5, 19, 20].
Increased expression of CK7, CK14, and CK19 in post-TACE HCC was also noted by Nishihara et al. [20]. They reported higher rates of intrahepatic metastases, poorly differentiated histology, multinucleated giant cells, and mitotic activity in comparison with untreated tumors.
A possible explanation was the phenomenon of selection pressure resulting from the locoregional treatment on tumor cells initially HCC, leading to an activation of the progenitor cells and a shift in the cholangiocytic direction, and therefore to a form of drug resistance. In fact, different local and systemic phenomena have been highlighted following locoregional ablative treatments: From the increase of circulating serum VEGF following partial ablation, which induces angiogenesis in the residual tumor, to the loss of expression of adhesion molecules (E-cadherin) with entry into the bloodstream of neoplastic cells, inhibition of apoptosis through enhanced expression of p53, to systemic immune modulation [20, 24–26].
More recently, an important role in differentiation in one direction or another has been attributed to the hepatic immunological microenvironment, and this may also be relevant in determining the true origin of cHCC-CCA. After hepatic injury, many types of cell necrosis can occur; the type of cell death can be more or less immunogenic, causing an immunologic systemic response but also determining the type of tumor. Hepatocytes in an apoptotic microenvironment give rise to the development of HCC; whereas in a necroptotic microenvironment, the same hepatocytes, identically containing oncogenic drivers, give rise to CCA. Moreover, the genetic or pharmacological suppression of the necroptosis pathway and the consequent cytokine cascade are able to make the type of growth reversible [27–29].
2.2 Classification
Given the coexistence of two tumor types, which, according to the new classification, must not only coexist but must be in deep conjunction, some theories have been developed on the pathogenesis of this neoplasm.
The last WHO classification [1] (see Table 1) excluded the collisional type, cholangiolocellular carcinoma, and fibrolamellar tumor, which were previously included in the classifications of Allen and Lisa [2](see Table 2) and Goodman et al. (see Table 3), basically considering only the transitional type (type II of Goodman and type C of Allen and Lisa) [1, 30].
WHO 2019
cHCC-CCA
Tumors showing varying degrees of hepatocytic and cholangiocytic cytological and architectural features either admixed or present as separate areas within the same tumor, are referred to as cHCC-CCA which there are varying degrees of hepatocytic and cholangiocytic cytologies and architectures, either admixed or as separate areas within the same tumor, are referred to as cHCC-CCA.
Intermediate cells
Primary liver carcinoma (PLC) with intermediate cells features or intermediate cell carcinoma,” referred to as intermediate cell carcinoma. These rare tumors contain relatively monomorphic populations of malignant epithelial cells that are phenotypically neither classic HCC nor classic intrahepatic CCA (iCCA). Immunophenotypically, they display variably mixed hepatocytic and cholangiocytic markers on a cellular basis.
Cholangiolocarcinoma
Primary liver carcinoma corresponding to cholangiolocarcinoma (CLC).
Table 1.
Classification according to WHO 2019.
Source: WHO classification [1].
Allen and Lisa (1949)
Type A
HCC and CCA are present at different sites in the same liver
Type B
HCC and intrahepatic CCA (iCCA) are present at adjacent sites
Type C
HCC and iCCA are combined within the same tumor
Table 2.
Classification according to Allen and Lisa.
Goodman et al. (1985)
Type I (collision tumor)
Presence of both HCC and iCCA in the same liver.
Type II (transitional tumor)
There is a transition from elements of HCC to elements typical of iCCA.
Type III (fibrolamellar tumor)
Resembles the fibrolamellar sub-type of HCC. Mucin-producing pseudoglands.
Table 3.
Classification according to Goodman et al.
The new classification has also attempted to simplify some morphological aspects, such as subtypes for stem cell features; a recent consensus proposes mentioning only whether the presence or absence of stem cell features is observed. The presence of stem cells is important but not decisive, contrary to what is categorized in the WHO 2010 classification (see Table 4), as they can also be present in HCC [8, 31].
WHO 2010
Type I (classical type)
Single tumor with both differentiations
Type II (with stem cell features)
cHCC-CCA with stem cell features, typical subtype
cHCC-CCA with stem cell features, intermediate-cell type
cHCC-CCA with stem cell features, cholangiolocellular subtype.
Table 4.
Classification according to WHO 2010.
The same consensus states that the diagnosis is carried out only with morphological evaluation and H&E staining, while immunohistochemistry is considered additional. At the same time, there is no percentage cut-off for one cell type or the other, and being a heterogeneous mass, it is recommended to perform large multiple biopsies in different areas for a more accurate histological diagnosis [32].
3. Diagnosis
cHCC-CCA has similar risk factors to HCC, even though the prevalence of cirrhosis is intermediate between HCC and CCA; cHCC-CCA also occurs in fibrosis, liver disease, or de novo. Several studies have highlighted risk factors such as male gender, cirrhosis, hepatitis infection, family history of liver cancer, heavy alcohol consumption, and diabetes mellitus [3].
But there are geographical differences in the definition of risk factors concerning the presence or absence of cirrhosis, the etiology of liver disease, and reflecting variability in the prevalence of infectious agents (hepatitis viruses and liver flukes), as well as lifestyle and nutritional differences [33].
Western studies tend more toward assimilating the cHCC-CCA to CCA, and the link with the presence of cirrhosis and chronic liver disease seems less evident than the evidence of Eastern studies, which see a greater correlation with liver viral infections and cirrhosis in an etiological framework more similar to HCC [5, 16, 34] particularly for the prevalence of HBV infection and male gender when compared to CCA. In Western reports, it seems more related to HCV infection, with less predominance of male gender and a lower prevalence of virus B infection compared to virus C infection [3].
Furthermore, several researchers have described that cHCC-CCA has a poor prognosis and exhibits more aggressive behavior compared to HCC and/or CCA alone.
The onset of an acute injury on chronic injury, causing a drift in cell differentiation after locoregional subtherapeutic treatment, and the hepatic microenvironment, more or less necroptotic or apoptotic, have been shown to possibly be involved in the pathogenesis [35].
Pre-treatment diagnosis is essential because the treatments, not yet standardized, provide a direction-oriented HCC or CCA. The choice of the type of surgical treatment is different; there is no consensus on lymphadenectomy, for example, and liver transplantation is still under discussion, while the choice of major hepatectomy seems consolidated with the preoperative diagnosis of cHCC-CCA.
An increase in both alpha-fetoprotein (AFP) and CEA occurs in 15% of CHC cases. However, generally, the increase in AFP is smaller than the increase in HCC. The diagnosis of cHCC-CCA can be suggested in cases of discordance between radiological features and tumor markers [36, 37]. The use of nestin expression as a biomarker of cHCC-CCA with a prognostic stratification role has recently been proposed.
While it seems to be useful, with good performance in differentiating between HCC and cHCC-CCA more than in differentiating between cHCC-CCA and CCA, the extent of its expression also seems to correlate with prognosis, since nestin-high tumors (>30% neoplastic cells with positive staining) showed worse outcomes [38].
Preoperative diagnosis of cHCC-CCA can be challenging based on imaging features alone.
Dynamic contrast-enhanced imaging plays a central role in the non-invasive diagnosis of primary liver cancers, such as HCC and CCA, whose appearances are well known with typical features on contrast-enhanced MRI and CT. Conversely, as cHCC-CCA usually demonstrates histological characteristics of both HCC and CCA, the imaging features of cHCC-CCA may also present a mixture of those seen in HCC and CCA, making a correct diagnosis complicated. cHCC-CCA may show features typical of HCC, such as non-rim arterial phase hyperenhancement (APHE), non-peripheral “washout,” and enhancing “capsule,” whereas other regions within the tumor could show progressive or delayed enhancement, necrosis, and ductal dilation more related to CCA [37].
Moreover, as HCC can be diagnosed and treated in high-risk patients based solely on non-invasive imaging findings without histological confirmation, it is crucial to differentiate non-HCC malignancies (i.e., CCA, cHCC-CCA) from HCC in order to determine if a biopsy is necessary or if patients should be treated as HCC.
The Liver Imaging Reporting and Data System (LI-RADS) is a classification system for liver lesions based on contrast material–enhanced CT and MRI imaging features (enhancement pattern and ancillary imaging findings). It is used in patients at elevated risk for primary liver cancers in order to identify or differentiate HCC from other less common non-HCC malignancies (i.e., CCA, cHCC-CCA), but it does not include specific guidelines for the diagnosis of cHCC-CCA [39].
Using the LI-RADS system, category LR–M is used for those lesions with either a targetoid appearance (rim APHE, peripheral “washout” appearance, delayed central enhancement, and a targetoid appearance on diffusion-weighted, transitional-phase, or hepatobiliary phase images) or a non-targetoid appearance with certain characteristic features (infiltrative appearance, marked diffusion restriction, necrosis or severe ischemia, or other features suggesting non-HCC malignancy). It allows the identification of cHCC-CCA, whose enhancement pattern and ancillary features resemble CCA more closely, making it necessary to perform a biopsy to obtain the diagnosis. On the contrary, category LR-4 and LR-5 should be used for those cHCC-CCA that exhibit more similarities to classical HCC; however, LR-5 categorization is considered definitive for HCC and does not require biopsy confirmation before treatment, resulting in cHCC-CCA tumors categorized as LR-5 being a false-positive finding. Some features might be helpful in differentiating these entities; in particular, biliary ductal dilation and capsular retraction are not classic imaging features of HCC but are more closely associated with CCA [39].
Furthermore, some reports [40–42] have suggested that tumor markers such as carbohydrate antigen (CA) 19-9 and AFP may be helpful in refining the differential diagnosis in the preoperative setting, showing cHCC-CCA simultaneous elevation of both markers or discordance between tumor marker elevation and imaging appearance (i.e., a tumor with a CCA imaging pattern seen in combination with elevated AFP, or vice versa, HCC imaging features combined with elevation of CA 19-9).
Although the prognosis remains controversial, recent studies [43, 44] have shown the prognostic value of imaging patterns in cHCC-CCA: tumors categorized as LR-4 or LR-5 (HCC mimicker) showed better survival outcomes than those categorized as LR–M (CCA mimicker).
At the same time, while the diagnostic accuracy of the biopsy alone has proven to be rather low, thanks to the combination of diagnostic imaging tools with histological examination on biopsy, the accuracy improves enormously, reaching 90% [44] (see Figures 1–5).
Figure 1.
Surgical piece: cHCC-CCA undergoing resection.
Figure 2.
This case represents a form of cHCC-CC. This lesion contains areas of both typical hepatocellular carcinoma and typical intrahepatic cholangiocarcinoma, with cytological and architectural features of hepatocellular carcinoma and distinctly an adenocarcinoma with malignant glands. Hepatocellular carcinoma component: Glutamine Synthetase (GS) positive; Alpha fetoprotein (AFP) positive. Intrahepatic cholangiocarcinoma component: Cytokeratin 7 (CK7) positive.
Figure 3.
Pathologically confirmed cHCC-CCA in a 69-year-old man. There is a huge hepatic mass with a (a) heterogeneous and (b) nodular aspect on T2-weighted images and on (c: out-of-phase; d: in-phase; e: pre-contrast phase) T1-weighted images due to the presence of necrosis. The mass shows only (f) minimal rim-like APHE, (g) no washout in the portal phase, with (h) gradual delayed peripheral enhancement on the transitional phase.
Figure 4.
Pathologically confirmed cHCC-CCA in a 79-year-old man with steatohepatitis. There is a hepatic mass in the right lobe with a heterogeneous appearance due to the presence of necrosis and a perilesional abscess cavity. The mass shows (a) inhomogeneous rim-like APHE, (b) only minimal washout in the portal phase, with (c) prevalent persistent delayed peripheral enhancement in the transitional phase.
Figure 5.
Pathologically confirmed cHCC-CCA in a 60-year-old man with HCV-related cirrhosis. There is a hepatic mass in the left lobe with a targetoid appearance on both the (a) arterial-phase and (b) portal phase, with (c) delayed peripheral enhancement on the transitional phase.
From the anatomopathological point of view, this is a rare hepatic primary tumor (with an incidence of 2%–5% among hepatic primaries) in which both differentiation in the sense of HCC and CCA within the same tumor, evidenced in hematoxylin–eosin staining, is unequivocally present. Immunohistochemistry is not necessary to define the prevalence of either component, and immunostaining is to be considered supplementary to morphological diagnostics. Morphological changes in HCC and CCA may both be present and closely intermingled or present in different areas of the tumor, with the frequent presence of cells with transitional aspects [4]. There is no minimum amount of hepatocytic and cholangiocytic components needed to define cHCC-CCA diagnosis. The presence of intracytoplasmic inclusions of hyaline material and/or steatosis that may be present in the fusion areas between the two morphological types can make histologic characterization difficult. Several studies have identified TERT and TP53 as the most frequently occurring gene mutations in this tumor type, the latter of which appears to have a correlation with tumor size [45].
Given the complex heterogeneity of the tumor itself, methods such as MALDI (matrix-assisted laser desorption ionization) and MSI (mass spectrometry imaging) have been studied for a definition at a higher level than histological definition alone [46].
Recently, attention has been drawn to the role of artificial intelligence as a diagnostic aid, given the complexity of the picture. A recent, interesting paper published in Nature Communications highlighted how the reclassification toward greater similarity to HCC rather than CCA, obtained with this system, is not entirely superimposable on that carried out in the laboratory, as it is not limited to analyzing the prevalence in quantitative terms of one morphological component over the other, with repercussions on both prognostication and the choice of therapeutic address [47].
4. Treatment
There are no standard guidelines for the treatment of cHCC-CCA. This is due to the rarity of the pathology and, therefore, to the absence of studies with significant numbers and to changes in classifications, which have altered diagnostic criteria over the years. Resective surgery remains the treatment of choice where possible; candidacy for transplantation, on the contrary, remains highly controversial. Locoregional therapies find space when there is no candidacy for resection [43] (see Figure 1).
The available studies are often retrospective studies with many limitations. Transplant patients are generally individuals in whom there has been an initial misdiagnosis that has made them candidates.
In a major 2020 review by Torzilli and colleagues [30], it was found that DFS and OS are worse in cHCC-CCA than HCC for both resected and transplant patients, defining this tumor as more similar to intrahepatic CCA rather than HCC.
Major hepatectomy, when feasible, and a resection margin greater than 1 cm have been shown to offer better results; since invasion to lymph nodes seems to be similar to CCA, lymphadenectomy has been proposed to reach oncological radicality, but whether lymphadenectomy is necessary to improve prognosis is still a matter of debate [48–51].
A recent study by Wang et al. [50] showed the prognostic improvement of anatomical resections in the case of tumors between 2 and 5 cm, similar to what happens with HCC, while this correlation is lost for tumors greater than 5 cm.
As reported by Zhou et al. [51], after propensity score matching, cHCC-CCA has shown a better outcome than HCC, comparable to CCA.
Holzner et al. [34] published an interesting work in 2020, carried out on a large cohort of patients, highlighting that although cHCC-CCA generally has worse aspects in terms of differentiation and vascular invasion compared to HCC, if matched both in size and by substantive cirrhosis, this does not necessarily translate into a worse outcome after resection.
Similarly, although currently cHCC-CCA is a contraindication to transplantation, it has been observed in cases that have undergone transplantation with an initial misdiagnosis that, for well-differentiated to moderately-differentiated histotypes of cHCC-CCA, the recurrence is only minimally increased, whereas there are no differences in OS and RFS [52–54].
A propensity score matching analysis by Chen et al. [55] proposed a risk scoring model to stratify risk in cHCC-CCA patients in relation to transplant candidacy, based on the peculiarity of the cHCC-CCA itself. It has been shown that although the tumor has a greater probability of causing vascular invasion due to similarities with CCA, a portion of these patients, based on the score, can still be considered at low risk, reopening the discussion on the complete a priori exclusion from this therapeutic possibility [55].
Tumor size greater than 5 cm, satellite nodules, vascular invasion, lymph node positivity, high tumor stage, high levels of CA 19-9, and surgical resection margins less than 2 cm represent negative prognostic factors [32, 48–51]. Although surgery remains the main treatment, diagnosis is often made at an advanced stage of the disease. An improvement in the chances of survival can be offered by locoregional therapies.
The studies available are carried out on small groups, given the rarity of the disease, but the use of locoregional techniques can offer both a treatment in cases of advanced disease and make advanced disease resectable. The difference in histological features compared to HCC predisposes to a lower efficacy of TACE or PEI due to lower vascularization and greater fibrosis. In addition, combined therapies can be hypothesized in order to treat the HCC component with locoregional techniques and platinum-based systemic therapy [56].
Mukund et al. [57] and Kim et al. reported that vascularization is a key feature in determining the effectiveness of locoregional treatments. In fact, greater vascularization makes the therapy more effective, becoming a prognostic factor for better response [57–59].
Regarding systemic treatments, it is interesting to note that generally effective therapies for HCC and CCA appear to have little efficacy in cHCC-CCA, suggesting a completely unique nature of this tumor [60].
Platinum-based therapy appears to be most effective in combination with other drugs in the treatment of unresectable HCC-CCA. However, the evolution of therapy for other primary liver tumors opens up the prospect of combined and personalized therapies using immunotherapy. An interesting study by Nguyen identifies the division of two types (immune-high subtype and immune-low subtype) according to susceptibility to immunotherapy treatment [45, 61].
A recent position paper by the EASL defines resective surgery as the only curative strategy, but no indication is given for lymphadenectomy because, given the rarity of the disease and the anatomy of hepatic lymphatic drainage, there is no strong specific recommendation, as is the case for liver transplantation (see Figure 6) [62].
Figure 6.
Rare primary liver cancers. An EASL position paper. [62].
Interesting prospects seem to be coming from three-dimensional organoid cultures; as the tumoroids derived from these studies maintain the molecular characteristics of the primary tumor, they seem to provide opportunities for studies on personalized therapies [63].
Molecular analysis has been hypothesized to address the best systemic treatment for advanced disease in either HCC-oriented or CCA-oriented treatment [64].
5. Conclusions
cHCC-CCA is a rare primary liver tumor with features of hepatic and portal vein invasion typical of HCC and lymphatic invasion typical of CCA, but with its own identity. The bi-phenotypic nature, above all in a variable percentage, makes it a challenge both from the diagnostic and therapeutic point of view.
Due to the rarity of the disease and the prognosis, generally considered inferior to that of HCC, surgical resection remains the only therapeutic treatment, while other treatments, such as transplantation, are still controversial.
The presence of cirrhosis or advanced disease considerably limits the number of patients actually eligible for oncologically curative resections.
The possibility of having diagnostic and prognostic biomarkers, as recently hypothesized for nestin, is indispensable in order to make a diagnosis, stratify the risk, and correctly expand the therapeutic possibilities.
Acknowledgments
The first version was published as a pre-print and was not peer-reviewed, with the title “Combined Hepatocholangiocarcinoma: Unresolved Points.” Minireview. Authorea, on December 27, 2024. DOI: 10.22541/au.173531958.83673188/v1
Conflict of Interest
The authors declare no conflict of interest.
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