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Cholangiolocarcinoma (CLC) is a primary liver carcinoma that resembles the canals of Hering and that has been reported to be associated with stem cell features. Due to its rarity, the nature of CLC remains unclear, and its pathological classification remains controversial. To clarify the positioning of CLC in primary liver cancers and identify characteristics that could distinguish CLC from other liver cancers, we performed integrated analyses using whole‐exome sequencing (WES), immunohistochemistry, and a retrospective review of clinical information on eight CLC cases and two cases of recurrent CLC. WES demonstrated that CLC includes IDH1 and BAP1 mutations, which are characteristic of intrahepatic cholangiocarcinoma (iCCA). A mutational signature analysis showed a pattern similar to that of iCCA, which was different from that of hepatocellular carcinoma (HCC). CLC cells, including CK7, CK19, and EpCAM, were positive for cholangiocytic differentiation markers. However, the hepatocytic differentiation marker AFP and stem cell marker SALL4 were completely negative. The immunostaining patterns of CLC with CD56 and epithelial membrane antigen were similar to those of the noncancerous bile ductules. In contrast, mutational signature cluster analyses revealed that CLC formed a cluster associated with mismatch‐repair deficiency (dMMR), which was separate from iCCA. Therefore, to evaluate MMR status, we performed immunostaining of four MMR proteins (PMS2, MSH6, MLH1, and MSH2) and detected dMMR in almost all CLCs. In conclusion, CLC had highly similar characteristics to iCCA but not to HCC. CLC can be categorized as a subtype of iCCA. In contrast, CLC has characteristics of dMMR tumors that are not found in iCCA, suggesting that it should be treated distinctly from iCCA. © 2024 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Introduction: Cholangiolocellular carcinoma (CoCC) resembles cholangiocellular carcinoma (CCC) and presents a variety of imaging findings; thus, preoperative diagnosis is often difficult. Methods: We retrospectively studied patients who were diagnosed with CoCC at the Kansai Rosai Hospital from 2006 to 2021 and treated by laparoscopic liver resection (LLR) or open liver resection (OLR). Result: Among 918 liver resections, 15 patients were diagnosed with CoCC: 11 underwent LLR and 4 OLR. For LLR and OLR, respectively, patient age was 69.9 ± 6.8 and 72.8 ± 10.6, sex was M/F: 10/1 and 2/2, Child‐Pugh was A/B/C: 10/1/0 and 4/0/0, liver damage was A/B/C: 8/3/0 and 4/0/0, preoperative diagnosis was CoCC/CCC/HCC: 1/2/8 and 2/2/0, pathological stage of Union for International Cancer Control (UICC) was IA/IB/II/IIIA/IIIB/IV: 8/0/2/1/0/0 and 0/0/3/0/1/0 (p =.0312), and extent of liver resection was Hr0/HrS/Hr1/Hr2/: 3/0/5/3 and 1/1/0/2. In LLR and OLR, respectively, operation time was 417.5 ± 191.0 and 407.5 ± 187.9 min, blood loss was 123.3 ± 217.4 and 1385.0 ± 1038.7 mL, and postoperative hospital stay was 12.2 ± 13.7 and 15.0 ± 6.6 days. For stages I and II/III, respectively, the 5‐year disease‐free survival rates were 100.0% and 34.3%, and the 5‐year overall survival rates were 100.0% and 55.6%. For stage II/III LLR and OLR, respectively, the 3‐year disease‐free survival rates were 33.3% and 37.5% (p =.8418), and the 5‐year overall survival rates were 66.7% and 50.0% (p =.8084). Conclusion: Although further studies are still needed to confirm, minimally invasive liver resection without lymph node dissection is one of a safe and effective approach to the management of CoCC. [ABSTRACT FROM AUTHOR]

Abstract Background Cholangiolocellular carcinoma (CoCC) is a relatively rare primary liver tumor. We present a literature review and case report of a patient who presented with a slow-growing CoCC that was completely resected after a 5-year follow-up period. Case presentation The patient was a 66-year-old man with a history of inflammatory thoracic and intra-abdominal pseudo-tumors. He was regularly followed up at our hospital for partial dilation of the pancreatic duct branch located in the body of the pancreas. Five years earlier, computed tomography (CT) demonstrated a small tumor in liver segment 4. Radiological findings were suggestive of hemangioma. Tumor size gradually increased during the 5-year follow-up period. CT scans showed that the tumor had progressed in size from 10 to 20 mm. Positron emission tomography CT revealed an accumulation of fluorodeoxyglucose (standardized uptake value max 5.3) at the tumor site. The tumor exhibited high intensity on T2-weighted and diffusion-weighted images of ethoxybenzyl magnetic resonance imaging. The tumor showed high intensity during the early phase but low intensity during the hepatobiliary phase. Tumor markers were within their respective normal ranges. Suspecting intrahepatic cholangiocarcinoma, left hepatectomy was performed. The tumor was diagnosed as CoCC based on pathological findings. The patient’s post-operative course was uneventful. The patient survived for a year, without any recurrence. Conclusions In cases dealing with small tumor sizes, it is difficult to distinguish between CoCC and hemangioma due to their similar radiological findings. Thus, it is important to consider the diagnosis of CoCC in small benign hepatic tumors. As such, follow-up radiological examination is recommended.

Abstract Background Cholangiolocellular carcinoma (CoCC) is an extremely rare disease comprising less than 1% of all primary malignant liver tumors. No effective treatment other than resection has been established. Herein, we report a case of locally advanced CoCC diagnosed as unresectable, which was successfully treated with curative resection after downsizing chemotherapy. Case presentation A 59-year-old Japanese woman with chronic hepatitis B was diagnosed with locally advanced intrahepatic cholangiocellular carcinoma. As it was difficult to perform R0 resection in the local hospital, chemotherapy combined with gemcitabine plus cisplatin was administered every 3 weeks. After a total of 10 courses of chemotherapy over 10 months the tumor was shown to be reduced in size by computed tomography imaging, and she was referred to our department for surgical resection. The effect of chemotherapy was classified as a “partial response” in the response evaluation criteria of solid tumors. After adding one course of chemotherapy, an extended left hepatectomy with resection of the caudate lobe was performed. R0 resection was achieved. Based on the pathological findings, the final diagnosis of CoCC was determined and eight courses of S-1 adjuvant chemotherapy were administered. At 14 months after the operation, the patient was alive without tumor recurrence. Conclusions Downsizing chemotherapy with gemcitabine and cisplatin may be an effective treatment strategy in locally advanced CoCC. Further evidence is required to establish an optimal strategy for the treatment of locally advanced CoCC.

Background: Cholangiolocellular carcinoma (CoCC) is a relatively rare primary liver tumor. We present a literature review and case report of a patient who presented with a slow-growing CoCC that was completely resected after a 5-year follow-up period. Case presentation: The patient was a 66-year-old man with a history of inflammatory thoracic and intra-abdominal pseudo-tumors. He was regularly followed up at our hospital for partial dilation of the pancreatic duct branch located in the body of the pancreas. Five years earlier, computed tomography (CT) demonstrated a small tumor in liver segment 4. Radiological findings were suggestive of hemangioma. Tumor size gradually increased during the 5-year follow-up period. CT scans showed that the tumor had progressed in size from 10 to 20 mm. Positron emission tomography CT revealed an accumulation of fluorodeoxyglucose (standardized uptake value max 5.3) at the tumor site. The tumor exhibited high intensity on T2-weighted and diffusion-weighted images of ethoxybenzyl magnetic resonance imaging. The tumor showed high intensity during the early phase but low intensity during the hepatobiliary phase. Tumor markers were within their respective normal ranges. Suspecting intrahepatic cholangiocarcinoma, left hepatectomy was performed. The tumor was diagnosed as CoCC based on pathological findings. The patient's post-operative course was uneventful. The patient survived for a year, without any recurrence. Conclusions: In cases dealing with small tumor sizes, it is difficult to distinguish between CoCC and hemangioma due to their similar radiological findings. Thus, it is important to consider the diagnosis of CoCC in small benign hepatic tumors. As such, follow-up radiological examination is recommended. [ABSTRACT FROM AUTHOR]

Inflammatory pseudotumor (IPT) is a benign tumor mass composed of chronic infiltration of inflammatory cells and fibrous tissue. IgG4-RD (related disease) in the hepatobiliary system has been widely recognized and includes IgG4-related hepatic IPT. This report describes a patient with IgG4-related hepatic IPT with sclerosing cholangitis. A 75-year-old woman was admitted to our hospital for the treatment of rectal cancer. Abdominal contrast-enhanced computed tomography revealed a low-density mass, 2.5 cm in diameter, in the left lateral lobe. Magnetic resonance imaging showed that the mass was slightly hypointense on T1-weighted images and slightly hyperintense on T2-weighted images. Based on these results, we made a diagnosis of cholangiolocellular carcinoma, and we performed a left hepatectomy. Histopathological examination showed that the mass was composed of fibrous stroma with dense lymphoplasmacytic infiltration. Immunohistochemically, IgG4-positive plasma cells were observed. The final diagnosis was IgG4-related hepatic IPT with sclerosing cholangitis. IgG4-related IPT is a relatively rare disease that can occur in any organ of the body. Although the accurate diagnosis of IgG4-related hepatic IPT remains difficult, IgG4-RD should be included in the differential diagnosis of liver tumors and histological analysis performed. [ABSTRACT FROM AUTHOR]

Abstract Background Cholangiolocellular carcinoma (CoCC) is a rare primary liver tumor that shows mass-forming growth in most cases. At present, no effective treatment for hepatic recurrence CoCC has been established. We present a case involving a patient with recurrent disease that showed an intraductal growth (IG type) pattern of recurrence. The patient was treated with repeat hepatectomy with bile duct reconstruction. Case presentation The patient was a 76-year-old man with a history of S8 subsegmentectomy for CoCC. At 8 months after surgery, tumor marker elevation was observed. Computed tomography revealed a tumor occupying the right hepatic duct (B5-8) to B4 and the junction of the cystic duct. Endoscopic retrograde cholangiopancreatography (ERCP) and a thrombus biopsy with peroral cholangioscopy (POCS) confirmed the recurrence of CoCC in the intrahepatic bile duct. Although extended right lobectomy with extrahepatic bile duct resection was the optimal curative procedure, it was thought that it would be difficult due to his poor liver function. However, a slow-glowing recurrent tumor blocked the posterior branch of the portal vein; thus, the right liver lobe gradually shrank, and the estimated remnant liver volume increased in response, allowing curative surgery to finally be performed. At 10 months after surgery, the patient is alive without recurrence. Conclusions We reported a case of IG-type recurrence in the bile duct, which is an unusual pattern of intrahepatic recurrence, after initial surgery for CoCC. A slow-growing recurrent tumor exerted similar effects to PVE, which allowed for curative surgery to be performed.

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a tumour that exhibits both hepatocytic and biliary differentiation. Classical risk factors for hepatocellular carcinoma (HCC) seem to also predispose patients to the development of cHCC-CCA. The pathological definition of cHCC-CCA has significantly evolved over time. The last 2019 WHO classification highlighted that the diagnosis of cHCC-CCA should be primarily based on morphology using routine stainings, with additional immunostaining used to refine the identification of subtypes. Among them, "intermediate cell carcinoma" is recognised as a specific subtype, while "cholangiolocellular carcinoma" is now considered a subtype of iCCA. Increasing molecular evidence supports the clonal nature of cHCC-CCA and parallels its biphenotypic histological appearance, with genetic alterations that are classically observed in HCC and/or iCCA. That said, the morphological diagnosis of cHCC-CCA is still challenging for radiologists and pathologists, especially on biopsy specimens. Identification of cHCC-CCA's cell of origin remains an area of active research. Its prognosis is generally worse than that of HCC, and similar to that of iCCA. Resection with lymph node dissection is unfortunately the only curative option for patients with cHCC-CCA. Thus, there remains an urgent need to develop specific therapeutic strategies for this unique clinical entity. [ABSTRACT FROM AUTHOR]

Background: Cholangiolocellular carcinoma (CoCC) is an extremely rare disease comprising less than 1% of all primary malignant liver tumors. No effective treatment other than resection has been established. Herein, we report a case of locally advanced CoCC diagnosed as unresectable, which was successfully treated with curative resection after downsizing chemotherapy. Case presentation: A 59-year-old Japanese woman with chronic hepatitis B was diagnosed with locally advanced intrahepatic cholangiocellular carcinoma. As it was difficult to perform R0 resection in the local hospital, chemotherapy combined with gemcitabine plus cisplatin was administered every 3 weeks. After a total of 10 courses of chemotherapy over 10 months the tumor was shown to be reduced in size by computed tomography imaging, and she was referred to our department for surgical resection. The effect of chemotherapy was classified as a "partial response" in the response evaluation criteria of solid tumors. After adding one course of chemotherapy, an extended left hepatectomy with resection of the caudate lobe was performed. R0 resection was achieved. Based on the pathological findings, the final diagnosis of CoCC was determined and eight courses of S-1 adjuvant chemotherapy were administered. At 14 months after the operation, the patient was alive without tumor recurrence. Conclusions: Downsizing chemotherapy with gemcitabine and cisplatin may be an effective treatment strategy in locally advanced CoCC. Further evidence is required to establish an optimal strategy for the treatment of locally advanced CoCC. [ABSTRACT FROM AUTHOR]

Abstract Background The incidence of synchronous double primary hepatic cancers is extremely low. Cholangiolocellular carcinoma is also a rare disease. Case presentation A 58-year-old Japanese man was referred to our hospital for the treatment of multiple liver tumors revealed on computed tomography scans. He was hepatitis B and C positive and had undergone hemodialysis for 9 years due to chronic renal failure. Computed tomography scans revealed two hepatic tumors (each ≤ 1.0 cm in diameter) in segments 3 and 7. The preoperative diagnosis was multiple hepatocellular carcinomas. He underwent partial resections of his liver. The resected specimens revealed that the tumors in segments 3 and 7 were well-defined lesions of 8.0 mm and 14.0 mm, respectively. Pathological and immunohistochemical examinations confirmed the tumor in segment 3 to be a cholangiolocellular carcinoma and the tumor in segment 7 to be a hepatocellular carcinoma. Chronic inflammation could contribute to the different types of primary hepatic cancers. It may also give rise to various combinations of synchronous double primary hepatic cancer in patients with chronic liver disease. Conclusions We describe the sixth case of synchronous double primary hepatic cancers consisting of hepatocellular carcinoma and cholangiolocellular carcinoma in chronic damaged liver and review the literature. In patients with chronic liver disease, careful surveillance with imaging studies should be mandatory as various types of primary hepatic cancers could develop.

During routine ultrasound examination, a hyperechoic mass was detected in the anterior segment of the liver in an 80-year-old woman with hepatitis C virus-related cirrhosis. Computed tomography and magnetic resonance imaging findings suggested a malignant tumor with abundant fibrous stroma, similar to cholangiolocellular carcinoma. However, subsequent partial hepatectomy revealed a mass characterized by abundant fibrosis without tumor cells, dilated blood vessels, and marginal ductular reaction. Accordingly, focal confluent fibrosis was diagnosed. Generally, the diagnosis of focal confluent fibrosis is straightforward because of its well-established imaging characteristics. However, its differentiation from a malignant tumor can occasionally be difficult because of variation in presentation depending on the amount of fibrous stroma and the degree of inflammatory cell infiltration. In the present case, diagnosis was difficult because the lesion was more localized than usual, presenting a mass-like shape, and there was obvious hyperintensity on T2-weighted imaging and ring-shaped hyperintensity on diffusion-weighted imaging. Moreover, hepatic capsular retraction was indistinct, which can be one of the key findings of focal confluent fibrosis. When a hepatic mass is associated with a fibrous lesion, focal confluent fibrosis should be considered in the differential diagnosis, even though the lesion is associated with several atypical findings. [ABSTRACT FROM AUTHOR]

Aim: Cholangiolocellular carcinoma (CLC) is classified as a subtype of combined hepatocellular cholangiocarcinoma with stem‐cell features (CHC‐SC) in the latest World Health Organization classification. This subclassification of CHC‐SCs is controversial and the relevance of such classification is unclear. Methods: We analyzed a series of CHC‐SCs and intrahepatic cholangiocarcinoma (iCCA) to clarify the clinicopathological features and mutational status of each tumor. Results: Background liver disease, fibrosis stage, microvascular invasion, nodal metastasis, and IDH1/2 mutation status were associated with their histology. Compared with the intermediate cell subtype of CHC‐SC (CHCs‐SC‐int), CLCs were less frequently associated with chronic viral hepatitis, and showed lower levels of serum alpha‐fetoprotein. Compared with iCCAs, CLCs showed lower levels of serum carbohydrate antigen 19‐9 (CA19‐9) and a lower frequency of expression of S100P. Patients with iCCA showed worse overall survival than those with CLC or CHC‐SC‐int. In patients with iCCA, CLC, or CHC‐SC‐int, a histology of iCCA, microvascular invasion, and serum CA19‐9 value of >100 U/mL were significant poor prognostic factors for overall survival in univariate analysis. Multivariate analysis showed that a high serum CA19‐9 value was an independent poor prognostic factor for overall survival. Conclusions: Patients with CLC are likely to have a different etiology and mutational background from those with CHC‐SC‐int. Their clinicopathological manifestations are also different from those with classic iCCA. Our results suggest that CLC might be a distinct entity among primary liver carcinomas. [ABSTRACT FROM AUTHOR]

Abstract Background Cholangiolocellular carcinoma (CoCC) is a rare liver tumor arising from the canals of Hering found between the cholangioles and interlobular bile ducts. Although morphologically CoCC mimics intrahepatic cholangiocarcinoma (ICC), CoCC exhibits a unique intermediate biologic behavior between hepatocellular carcinoma (HCC) and ICC. Curative resection is required for prolonged survival in patients with CoCC. However, effective therapy for postoperative hepatic recurrence has not yet been standardized. Case presentation A 40-year-old man had an asymptomatic liver mass found during a regular medical examination. Contrast-enhanced computed tomography revealed a well-enhanced mass, 15 cm in diameter, in the right liver. He underwent right hemihepatectomy at a local hospital under the preoperative diagnosis of hepatocellular carcinoma. Pathologic examination confirmed a moderately differentiated tubular adenocarcinoma, leading to a diagnosis of ordinary ICC. Twelve months after surgery, he was referred to our hospital due to three hepatic recurrences in the left medial segment. He underwent partial hepatectomy for the recurrence, followed by adjuvant chemotherapy using gemcitabine alone. After the second hepatectomy, hepatic recurrences developed an additional seven times. The numbers and sizes of the recurrent tumors were very limited at each recurrence, satisfying the standard criteria for percutaneous radiofrequency ablation (RFA) for the treatment of HCC. All lesions were treated by percutaneous RFA, although this was an exceptional approach for ICC. He is now alive without evidence of disease 9.2 years after the first hepatectomy. Because his clinical outcome was satisfactory and not compatible with the typical negative outcomes of ordinary ICC, we re-reviewed the histological findings of his tumor. The tumor was composed of small gland-forming cells proliferating in an anastomosing pattern; the cell membrane was strongly immunoreactive for epithelial membrane antigen. These findings were in accordance with the typical features of CoCC, revising his final diagnosis from ICC to CoCC. Conclusions This case report demonstrates a satisfactory outcome using repeated local treatments, such as hepatectomy and RFA, for hepatic recurrences of CoCC, suggesting that a localized treatment approach can be considered to be a therapeutic option. We should be careful in making a definitive diagnosis of ICC and ruling out CoCC because the diagnosis potentially dictates the treatment strategy for recurrences.

Aim: The genetic profile of cholangiolocellular carcinoma (CLC) and its origin in relation to hepatocellular carcinoma (HCC) remain unclear. To elucidate the genetic profile of CLC, a comprehensive analysis of genetic mutations was carried out in a case of CLC with an HCC‐like focal area and metachronous HCC. Method: Liver tissue was obtained from CLC, a co‐existent HCC‐like area, and metachronously developed HCC by laser capture microdissection of formalin‐fixed paraffin‐embedded specimens obtained by hepatectomy. Gene mutational profiles were analyzed comprehensively by next‐generation sequencing and digital PCR. Relationships among gene profiles, immunohistochemistry, and clinicopathological findings were investigated. Results: Mutations in EGFR, PTEN, RB1, TP53, and ERBB2 were found in CLC, whereas mutations in KIT, BRAF, PTEN, TP53, and SMAD4 were found in the coexistent HCC‐like area. Only the mutation in PTEN has a common Catalogue of Somatic Mutations in Cancer ID in the CLC and coexistent HCC‐like area, and is related to the kinase‐RAS module. In contrast, no cancer‐related mutations were found in the metachronous HCC. No TERT mutations were found in any of the regions by digital PCR. Immunohistochemical staining for p53 was negative in CLC, although ≤10% positive in the coexistent HCC‐like area. Immunostaining of C‐kit, HER2, PTEN, and SMAD4 were negative. Conclusion: The genomic features of CLC and the focal area of an HCC‐like region differ, but are related to the kinase‐RAS module. The development of carcinogenesis in the CLC and HCC‐like areas in this case might differ, following a common PTEN mutation, although alteration of the kinase‐RAS module is the most common molecular event in CLC. [ABSTRACT FROM AUTHOR]

Background: Cholangiolocellular carcinoma (CoCC) is a rare liver tumor arising from the canals of Hering found between the cholangioles and interlobular bile ducts. Although morphologically CoCC mimics intrahepatic cholangiocarcinoma (ICC), CoCC exhibits a unique intermediate biologic behavior between hepatocellular carcinoma (HCC) and ICC. Curative resection is required for prolonged survival in patients with CoCC. However, effective therapy for postoperative hepatic recurrence has not yet been standardized. Case presentation: A 40-year-old man had an asymptomatic liver mass found during a regular medical examination. Contrast-enhanced computed tomography revealed a well-enhanced mass, 15 cm in diameter, in the right liver. He underwent right hemihepatectomy at a local hospital under the preoperative diagnosis of hepatocellular carcinoma. Pathologic examination confirmed a moderately differentiated tubular adenocarcinoma, leading to a diagnosis of ordinary ICC. Twelve months after surgery, he was referred to our hospital due to three hepatic recurrences in the left medial segment. He underwent partial hepatectomy for the recurrence, followed by adjuvant chemotherapy using gemcitabine alone. After the second hepatectomy, hepatic recurrences developed an additional seven times. The numbers and sizes of the recurrent tumors were very limited at each recurrence, satisfying the standard criteria for percutaneous radiofrequency ablation (RFA) for the treatment of HCC. All lesions were treated by percutaneous RFA, although this was an exceptional approach for ICC. He is now alive without evidence of disease 9.2 years after the first hepatectomy. Because his clinical outcome was satisfactory and not compatible with the typical negative outcomes of ordinary ICC, we re-reviewed the histological findings of his tumor. The tumor was composed of small gland-forming cells proliferating in an anastomosing pattern; the cell membrane was strongly immunoreactive for epithelial membrane antigen. These findings were in accordance with the typical features of CoCC, revising his final diagnosis from ICC to CoCC. Conclusions: This case report demonstrates a satisfactory outcome using repeated local treatments, such as hepatectomy and RFA, for hepatic recurrences of CoCC, suggesting that a localized treatment approach can be considered to be a therapeutic option. We should be careful in making a definitive diagnosis of ICC and ruling out CoCC because the diagnosis potentially dictates the treatment strategy for recurrences. [ABSTRACT FROM AUTHOR]

Objectives: To review the gadoxetic acid disodium (EOB)-enhanced magnetic resonance (MR) imaging features of cholangiolocellular carcinoma (CoCC) of the liver and compare them with those of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC).Methods: EOB-enhanced MR images of 19 patients with CoCC, 23 with ICC, and 51 with HCC were retrospectively evaluated qualitatively and quantitatively. Univariate and multivariate analyses were performed to determine the characteristic MR features of CoCC with histopathological-imaging correlation.Results: Multivariate logistic regression analysis showed that dot-/band-shaped internal enhancement during the arterial and portal phases (P < 0.001), and larger arterial ring enhancement ratio (CoCC, 0.13 ± 0.04; ICC, 0.074 ± 0.04; P = 0.013) were significantly independently associated with CoCC in contrast to ICC, whereas several MR features including progressive enhancement during the portal and late phases (P < 0.001), target appearance in the hepatocyte phase (P = 0.004), and vessel penetration (P = 0.013) were significantly more frequently associated with CoCC than HCC. The dot-/band-like internal enhancement (78.9% of CoCCs) histopathologically corresponded to the tumour cell nest with vascular proliferations and retained Glisson's sheath structure.Conclusions: EOB-enhanced MR features of CoCC largely differ from those of HCC but are similar to those of ICC. However, the finding of thicker arterial ring enhancement with dot-/band-like internal enhancement could help differentiate CoCC from ICC.Key Points: • Gadoxetic acid-enhanced MR features of cholangiolocellular carcinoma (CoCC) resembled those of intrahepatic cholangiocarcinoma (ICC). • Gadoxetic acid-enhanced MR features of CoCC largely differed from those of hepatocellular carcinoma. • Dot-/band-like internal enhancement of CoCC may be helpful for differentiating from ICC. • Arterial ring enhancement of CoCC was larger than that of ICC. [ABSTRACT FROM AUTHOR]

Introduction Cholangiolocellular carcinoma (CoCC) is thought to originate from hepatic stem cells. Its clinical characteristics, including radiological and prognostic factors, remain unclear. Presentation of case A 79-year-old woman with hypertension was admitted to our hospital after abnormal tumor marker levels were detected during an annual physical examination. Her laboratory data results were within normal range, and she was classified as Child-Pugh A. Enhanced computed tomography revealed a tumor located on the left side of the liver, with a maximum size of 60 mm. The tumor showed heterogeneously enhancing edges in the arterial phase, while prolonged tumor enhancement was detected in the delayed phase. Tumor penetration by the left hepatic artery was evident, whereas the left portal vein was invaded by the tumor. The preoperative diagnosis was cholangiocellular carcinoma. Left hepatectomy and cholecystectomy were performed with no postoperative complications; the final diagnosis was CoCC. Multiple liver metastases appeared 6 months after surgery; the patient is now receiving systematic chemotherapy. Discussion While portal vein penetration into CoCCs has been reported, the same is not true of the hepatic artery; therefore, this case illustrates a unique tumor growth pattern. Conclusion A unique growth pattern as well as a large primary tumor may contribute to earlier recurrence. [ABSTRACT FROM AUTHOR]

Aims Combined hepatocellular carcinoma and cholangiocarcinoma ( cHC- CC), which generally has a poor prognosis, comprises hepatocellular carcinoma ( HCC), cholangiocarcinoma ( CC), and diverse components with intermediate features between HCC and CC. Histological subtypes with stem cell ( SC) features (the SC subtype) have different clinicopathological significance in cHC- CC. The mutational status may reflect the clinicopathological subgroup of cHC- CC together with the histological subtype. Methods and results We examined the mutational statuses of KRAS, IDH1 or IDH2 ( IDH1/ 2), ARID1A, the TERT promoter, and TP53, and their relationships with clinicopathological features in 53 patients with cHC- CC. Background liver diseases were hepatitis B ( n = 9), hepatitis C ( n = 22), alcoholic liver disease ( n = 5), non-alcoholic fatty liver disease ( NAFLD) ( n = 8), and unknown ( n = 9). Mutations in KRAS, IDH1/ 2, ARID1A, the TERT promoter and TP53 were detected in four (7.5%), six (11.8%) seven (13.2%), 16 (31.3%), and 24 patients (45.3%), respectively. KRAS mutations correlated with higher histological diversity scores and a higher M-factor ( P < 0.05). ARID1A mutations correlated with alcoholic liver disease, smaller tumour size, a lower grade of coexistent HCC, and α-fetoprotein ( AFP) positivity, and were associated with cholangiolocellular carcinoma subtype predominance ( P < 0.05). TERT promoter mutations correlated with hepatitis B, an intermediate subtype-predominant histology, higher clinical stage, and a higher N-factor ( P < 0.05), and were associated with gender (female-predominant) and previous therapy. TP53 mutations correlated with AFP positivity ( P < 0.05). Conclusions The results of the mutational analysis revealed that cHC- CC has diverse types of mutations, and also that mutations in the TERT promoter and ARID1A may reflect aetiological impact, different histological subtypes, histogenesis, and tumour aggressiveness. These results suggest the potential efficacy of molecular-based subclassification of cHC-CC. [ABSTRACT FROM AUTHOR]

A 71-year-old man with alcoholic cirrhosis was found to have multiple hypervascular lesions in the liver on enhanced computed tomography. An ultrasound-guided biopsy of the lesion was performed. Immunohistochemical analysis for hepatocyte paraffin 1 expression was negative; cytokeratin (CK) 7, CK19, epithelial cell adhesion molecule and epithelial membrane antigens were positive; mucicarmine staining was negative. The tumor was thus histologically diagnosed as cholangiolocellular carcinoma (CoCC). The tumor was inoperable due to the associated advanced liver disease. In addition, the patient preferred systemic chemotherapy using only orally administered agents. Thus, S-1 monotherapy was recommended. S-1 was initially administered orally at a dose of 80 mg/day. Although the levels of tumor marker (prothrombin induced by vitamin K absence/antagonist-II and carbohydrate antigen 19-9) levels were marginally elevated, their values did not change over the entire course. The patient achieved a partial response according to the Response Evaluation Criteria In Solid Tumors (RECIST) and modified RECIST 1 year after chemotherapy initiation. In conclusion, S-1 monotherapy exhibited promising efficacy against unresectable CoCC. [ABSTRACT FROM AUTHOR]

Adenocarcinoma represents the most frequent biliary tract cancer. However, other rare histotypes can be found in the biliary tract, such as cholangiolocellular carcinoma, cholangiocarcinoma with ductal plate malformation pattern, adenosquamous carcinoma, mucinous carcinoma, signet ring cell carcinoma, clear cell carcinoma, mucoepidermoid carcinoma, lymphoepithelioma-like carcinoma, and sarcomatous cholangiocarcinoma. These cancer types account for less than 10 % of all the already rare biliary tract tumors. Yet, they represent a relevant issue in everyday clinical practice, given the lack of therapeutic recommendations and the overall scarcity of data, mainly deriving from isolated small center-specific cohorts of patients.The shifts of such histotypes from the most common ones reflect genetic and molecular differences, determine changes in clinical aggressiveness, and suggest a possible variability in sensitivity to the standard treatments of biliary adenocarcinomas. The consistency and degree of these variables are still to be solidly demonstrated and investigated. Therefore, this paper aims to review the current literature concerning very infrequent and rare epithelial biliary tract cancers, focusing our attention on the clinical, molecular, and immunohistochemical features of these tumors. [Display omitted] • Histologically, 90 % of epithelial BTCs are adenocarcinomas, whereas the remaining 10 % are constituted by rarer forms. • Despite the common anatomic origin, these histotypes differ in incidence, prognosis, and survival. • The knowledge of these less frequent histotypes is quite limited by the scarcity of numerous cohorts to be studied in depth • Due to their very low incidence and the lack of current treatment options, "molecular diagnosis" provides an essential opportunity for improved personalized treatment plans [ABSTRACT FROM AUTHOR]

Synchronous double cancers consisting of hepatocellular carcinoma (HCC) and cholangiolocellular carcinoma (CoCC) are extremely rare. We herein report a surgical case of synchronous double cancers in a patient with primary HCC and CoCC. A 45-year-old man with hepatitis B was admitted to our hospital with hepatic tumors. The level of protein induced by vitamin K antagonist (PIVKA-II) was found to be elevated. Computed tomography (CT) revealed a 23-mm tumor with early-phase enhancement and late-phase washout in the 6th segment of the liver, and a 10-mm tumor with slight early-phase enhancement and late-phase washout in the 7th segment of the liver. Magnetic resonance imaging (MRI) revealed that the two tumors in the 6th and 7th segments showed low intensity on T1-weighted images and high intensity on T2-weighted images. Based on those preoperative examinations, the liver tumors were diagnosed as multiple primary hepatocellular carcinomas. The patient underwent a posterior segmentectomy. A histopathological examination revealed that the tumor of the 6th segment of the liver was moderately differentiated HCC, and that the tumor of the 7th segment of the liver was CoCC. The postoperative course was uneventful. However, lymph node recurrence was observed 6 months later and the patient died 20 months after surgery. There are only six reported surgical cases of synchronous double primary liver cancers consisting of HCC and CoCC. We are of the opinion that curative resection may be an effective treatment for double cancer consisting of HCC and CoCC, and that it may provide long-term survival. [ABSTRACT FROM AUTHOR]

We report a case of combined hepatocellular-cholangiocarcinoma with stem cell features, cholangiolocellular subtype arising about 15 years after placement of an inferior vena cava stent for primary Budd–Chiari syndrome. Pre-surgical differentiation of the tumor from hepatocellular carcinoma was difficult because of elevated levels of alpha-fetoprotein and hypervascularity in the arterial phase. Histopathological examination revealed atypical cells forming ductal and alveolar structures showing a vague border with the surrounding liver. Immunostaining showed positive results for epithelial membrane antigen, mainly localized to the apical surface of the tubules, representing a characteristic finding for combined hepatocellular-cholangiocarcinoma with stem cell features, cholangiolocellular subtype. Combined hepatocellular- cholangiocarcinoma with stem cell features arising in the liver with hepatic damage from Budd–Chiari syndrome is not common, but diagnosis is important to manage the malignancy, which shows different clinical behaviors from hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer. Cirrhosis and chronic viral hepatitis are known to be important risk factors for ICC, especially the mass-forming (MF) type of ICC at the periphery of the liver. Cholangiolocellular carcinoma (CoCC) is a rare type of primary liver cancer, which is thought to originate from hepatic progenitor or stem cells. CoCC often exhibits the similar MF type at the periphery of the liver, as ICC, and CoCC is also associated with cirrhosis or chronic viral hepatitis. Better survival rates after surgery have been reported for ICC patients with chronic viral hepatitis than for those without chronic viral hepatitis, although survival rates did not differ significantly in relation to cirrhosis. On the other hand, patients with CoCC had better surgical results than those with MF-type ICC. This review summarizes the clinical characteristics and surgical outcomes of ICC and CoCC associated with cirrhosis or chronic viral hepatitis. [ABSTRACT FROM AUTHOR]

Backgrounds & Aims Combined hepatocellular-cholangiocarcinoma (c HC-CC), a malignant liver tumour with poor prognosis, is composed of hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and diverse components with intermediate features between HCC and CC, which correspond to hepatic progenitor cells. According to the WHO classification 2010, we surveyed the prevalence and clinicopathological significance of each subtype with stem-cell features [SC subtype; typical subtype (TS), intermediate cell subtype (INT) and cholangiolocellular type (CLC)] in c HC-CC and HCC. Methods Sixty-two patients with c HC-CC (19 women and 43 men) and 26 patients with HCC (all men) were examined. The prevalence of each component was histologically assessed with assistance of mucin and immunohistochemical stainings. Results SC subtypes were observed in all c HC-CCs in various amount and combination. The prevalence of each SC subtype in c HC-CC was as follows: TS, 10 (16.1%); INT, 53 (83.9%) and CLC, 44 (71.0%). The proportion of INT was significantly correlated with gender (female-dominant) ( P < 0.05), tumour size ( P < 0.05), histological grading of HCC ( P < 0.01) and inversely correlated with the degree of stromal fibrosis ( P < 0.05). The proportion of CLC was significantly correlated with the degree of fibrosis ( P < 0.01) and inflammation ( P < 0.01), and inversely correlated with tumour size ( P < 0.01) and histological grading of HCC ( P < 0.05). The proportion of TS was significantly inversely correlated with the degree of inflammation ( P < 0.01). Histological diversity score was significantly correlated with vascular invasion and the positivity for α-foetoprotein. Conclusion The proportion of each SC subtype was significantly associated with certain clinicopathological factors, suggesting different properties of each SC subtypes. [ABSTRACT FROM AUTHOR]

Intrahepatic cholangiocarcinomas (ICCs) are made up of heterogenous carcinomas arising from different anatomical sites of the liver. Two types of candidate stem/progenitor cells of the biliary tree are postulated to exist at the peribiliary glands for large bile ducts and at the canals of Hering for small ducts and hepatocytes. According to the recent observations, ICCs can be subclassified into two types: tumors involving the large bile ducts comparable in size to the intrahepatic second branches and composed of a tubular or papillary component with tall columnar epithelium, and tumors involving the smaller duct than segmental branches and composed of small tubules with cuboidal epithelium. Perihilar large duct type ICCs can be interpreted as arising from large bile duct type ICCs, and peripheral small duct type ICCs may arise from small bile duct type or ductular type ICCs. Chronic biliary inflammation induces neoplastic change of the large bile ducts and thereby progression to the perihilar large duct type ICC, which can be grossly classified into periductal filtrating type ICC and intraductal growth type ICC, while chronic hepatitis or cirrhosis induces mass‐forming peripheral small duct type ICC. The different morphological and molecular features, including stromal components and tumor vasculature, support the hypothesis that perihilar large duct type ICCs and peripheral small duct type ICCs arise from different backgrounds, have different carcinogenetic pathways, and exhibit different biologic behaviors. [ABSTRACT FROM AUTHOR]

Aim The aim of this study was to evaluate integrin expression and immunolocalization of the extracellular matrix proteins in cholangiolocellular carcinoma ( CoCC). Methods Tissue specimens of 23 CoCC, 28 cholangiocarcinomas ( CCC), 42 hepatocellular carcinomas ( HCC) and 11 classical type combined hepatocellular cholangiocarcinomas ( CHC) were immunostained for β6, β4 and α3 integrins, fibronectin and laminin. ITGB6, B4 and A3 mRNA levels in six HCC cell lines, five CCC cell lines and two CHC cell lines were quantified by quantitative reverse transcription polymerase chain reaction. Results Little or no positivity for β6, β4 and α3 integrins was shown in 91%, 91% and 52% of CoCC and 100%, 98% and 81% of HCC, respectively, according to immunostaining, whereas intense positive staining for these integrins was demonstrated in 64%, 96% and 75% of CCC, respectively. There was a close correlation between β4 and α3 integrin expression and intracytoplasmic laminin in CoCC, CCC and HCC, but not between β6 expression and its ligand, fibronectin. Integrin mRNA levels were increased in four of five CCC cell lines, but nearly undetectable in five of six HCC cell lines and one CHC cell line. Tubular differentiation of a CHC cell line cultured in collagen gel matrix induced upregulation of these integrins. Conclusion Our results first indicated downregulation of αvβ6, α6β4 and α3β1 integrins in CoCC, in contrast to its high expression in CCC, suggesting a diagnostic value of integrins in the differential diagnosis of CoCC and CCC, as well as a useful inducible marker of the intermediate features of CoCC. [ABSTRACT FROM AUTHOR]

Purpose: Cholangiolocellular carcinoma (CLC) is an extremely rare malignant liver tumor. It is thought to originate from the ductules and/or canals of Hering, where hepatic stem cells (HpSC) are located, but there are few reports on cancer stem cell markers in CLC. Thus, we evaluated the significance of cancer stem cell markers, including CD133, CD44, and EpCAM, in CLC. Methods: The subjects of this study were three patients with CLC and one patient with an intermediate type of combined hepatocellular cholangiocarcinoma (CHC). The cancer cell markers, CK7, CK19, and EMA, were evaluated immunohistochemically. Results: Histological examination of the CLC revealed morphologically cholangiolar features and immunohistochemical examination revealed positivity for CD133, CD44, and EpCAM. On the other hand, in the intermediate type of CHC, only CD44 was positive, whereas CD133 and EpCAM were negative. Conclusion: CLC may have stronger features derived from HpSCs than an intermediate type of CHC. [ABSTRACT FROM AUTHOR]

Although guidelines exist for routine screening for malignancy in adults with primary sclerosing cholangitis, no imaging guidelines exist for the pediatric population. Cholangiolocellular carcinoma is a rare malignant liver tumor that has been found in adults with chronic liver disease.We present a case of cholangiolocarcinoma found in an adolescent boy with small duct sclerosing cholangitis. The diagnosis of small duct sclerosing cholangitis was made at the age of 6 at which time he also had advanced fibrosis histologically, but no evidence of decompensation either clinically or biochemically. Several years after this diagnosis, a small liver lesion was found incidentally on computed tomography scan following a motorcycle accident. This lesion was shown to be stable by magnetic resonance imaging over the course of 2 years. At 15 years of age, magnetic resonance imaging findings changed with features suggestive of malignancy. This led to resection of the lesion. Pathologic examination confirmed the presence of cholangiolocarcinoma, a tumor found primarily in adults with a history of viral hepatitis. To our knowledge, this is the first such report in a pediatric patient. [ABSTRACT FROM AUTHOR]

Cholangiolocellular carcinoma (CoCC) is a rare malignant primary liver tumor that is considered to originate from the canals of Hering, where hepatic progenitor cells are located. CoCC has various clinicopathological findings, therefore it is difficult to describe a clear diagnostic criteria for CoCC. Reported is a case of a large CoCC in a 45-year-old Japanese woman, which could not be preoperatively diagnosed as CoCC. The final diagnosis of CoCC was determined by pathological observation. Since both the biological behavior and diagnostic criteria of CoCC remain unclear, it is necessary to accumulate more information on CoCCs in order to elucidate these characteristic findings. [ABSTRACT FROM AUTHOR]

The authors present an interesting case of a 60-year-old man who underwent right hepatectomy for a diagnosis of hepatocellular carcinoma (HCC) on a background of noncirrhotic chronic hepatitis C. Pathologic examination confirmed the presence of HCC near the porta hepatis, which invaded the right portal vein branch. In addition, a well- demarcated 13.57.84.0 cm yellow and firm area upstream of the HCC was noted. This yellow area corresponded to a tumoral ductular proliferation, which cytologically was extremely bland, but invaded portal tracts and the adjacent liver parenchyma. This tumoral proliferation mimicked ductular reaction, except that it had more anastomosing structures and was associated with abundant hyalinized fibrotic stroma. Cytologically, the tumor cells had round to oval nuclei with fine chromatin, indistinct nucleoli, and scant cytoplasm. They exhibited immunohistochemical features of hepatic progenitor cells, i.e., expressing CK7, CK19, and N-CAM; and their malignancy was supported by the p53 and Ki67 immunoreactivity. The authors concluded that the patient had cholangiolocellular carcinoma with an aggressive hepatocellular carcinoma component. Cholangiolocellular carcinoma has been reported to be associated with chronic hepatitis C viral infection and to derive from hepatic progenitor cells, which explains why hepatocellular carcinoma and/or cholangiocarcinoma component may be present. [ABSTRACT FROM AUTHOR]

Cholangiolocellular carcinoma (CLC) is a rare malignant primary liver tumor, categorized as a subtype of cholangiocellular carcinoma. CLC is considered to originate from hepatic progenitor cells, and sometimes accompanies a component of cholangiocellular carcinoma and/or hepatocellular carcinoma (HCC). We report herein a case of a 53-year-old Japanese male with CLC occurring asynchronously after a resection of HCC. At the age of 50, the patient underwent a first hepatectomy due to HCC, followed by intrahepatic recurrence. At 53, a new type of hepatic tumor was detected. Dynamic computed tomography revealed a multinodular enhanced tumor in the hepatic arterial phase, and an iso-density tumor in the portal venous and delayed phases. Living donor liver transplantation was performed for the treatment of this liver tumor because of his poor liver function. Histological findings confirmed the diagnosis of CLC. Nineteen months after the liver transplantation, bone metastasis of CLC was detected. Although the preoperative diagnosis of CLC is difficult in general, CLC should be considered as a differential diagnosis when a tumor with atypical image findings for HCC is observed after the resection of HCC. Once the diagnosis of CLC is made, postoperative surveillance of the patient must be performed, including the bone. [ABSTRACT FROM AUTHOR]

The frequency of double primary cancers in the liver is very low. All reported cases are double cancers consisting of hepatocellular carcinoma (HCC) and intrahepatic cholangiocellular carcinoma (CCC). We herein report a surgical patient who had simultaneous double cancers consisting of HCC and cholangiolocellular carcinoma (CoCC). This is the first case report of such a patient. A 70-year-old Japanese man was admitted to our hospital for further examination of two hepatic nodules. He had a history of schistosomiasis japonica, idiopathic pulmonary fibrosis, and diabetes mellitus. Laboratory data revealed that hepatitis C virus (HCV) antibody was positive and hepatic enzymes were slightly elevated. The level of prothrombin induced by vitamin K absence or antagonist II was elevated. Computed tomography depicted two tumors; one, measuring 4.0 cm in diameter, was in the medial segment and the other, 2.2 cm in diameter, was in the posterior superior segment of the liver. The larger tumor showed contrast enhancement and the smaller one showed enhancement at the tumor periphery in the hepatic arterial phase. In the portal phase, the larger tumor became less dense than the liver parenchyma, but the periphery of the smaller one showed continuous enhancement. He underwent an operation under a diagnosis of double hepatic cancers, consisting of HCC and CCC. However, microscopic examination of the resected tumors revealed that the larger tumor was moderately differentiated HCC and the smaller one was CoCC. [ABSTRACT FROM AUTHOR]