Clinicopathological features and surgical outcomes of cholangiolocellular carcinoma : a systematic review

Background: Colangiolocellular carcinoma (CoCC) is a rare type of primary malignant liver tumor. Patients and methods: We searched computed medical databases, ranging from 1959 to 2015, which described surgical resections of CoCCs. The clinicopathological data were evaluated for its association with hepatic CoCC, along with the prognosis for each patient and the surgical outcomes described in the case report. Results: We obtained clinicopathological data for 75 patients (46 men and 29 women), with a mean age of 64 years (range, 15-84 years), who had undergone surgical resections for CoCCs. Although CoCCs have similar clinicopathological features to hepatocellular carcinomas and/or cholangiocarcinomas, the treatment strategies in patients with CoCCs are identical to those used to treat other primary neoplasms of the liver. The immunohistochemical features of CoCC also included testing positive for epithelial membrane antigen. The overall 1-, 3-, and 5-year survival rates after surgery, for 75 cases with available data, were 92.4%, 65.9%, and 60.8%, respectively. Conclusions: To determine the best management strategy for this tumor and to improve the accuracy of prognosis for patients, we aim to continue to collect and analyze the epidemiological and pathological data for CoCCs.


INTRODUCTION
Cholangiolocellular carcinoma (CoCC) is a rare type of primary malignant liver tumor, which was first reported by Steiner and Higginson in 1959 (1).The incidence of CoCCs was reported to be 0.56% in patients with resected primary malignant liver tumors (2).The tumor is thought to be derived from hepatic stem cells, which exist in the canals of Hering (2)(3)(4)(5)(6)(7)(8)(9).CoCCs have been previously classified as a type of intrahepatic cholangiocarcinoma (10,11).
Currently, on the basis that combined hepatocellular-cholangiocarcinomas are derived from hepatic progenitor and/or stem cells (12), CoCC are classified, in the latest version of the World Health Organization (WHO) classification of the digestive system, as combined hepatocellular cholangiocarcinomas with stem cell features (13).In Japan, CoCCs are currently classified as independent primary malignant liver tumors along with the hepatocellular carcinoma, intrahepatic cholangiocarcinoma and combined hapetocellularcholangiocarcinoma according to the Liver Cancer Study Group of Japan, which has outlined general rules for the clinical and pathological studies of primary liver cancers in 2008 (14).In survival, hepatocellular carcinoma show better prognosis compared to both combined hepatocellularcholangiocarcinomas and intrahepatic cholangiocarcinoma after curative surgery.
Furthermore, the postoperative survival of combined hepatocellular-cholangiocarcinoma without stem cell features is thought to be worse than those of pure hepatocellular carcinoma, and similar to those of intrahepatic cholangiocarcinoma (15).However, the prognosis of CoCCs remains still unclear with conflicting evidence on small series and number of patients.Therefore, long-term follow-up of larger cohorts of strictly categorized tumors is needed to adequately define the clinical and biological behavior of all the combined variants.
We conducted a retrospective analysis of the currently published CoCC cases, to determine their clinicopathological features and the potential surgical outcomes, including survival rates, for patients with this uncommon tumor.

Eligibility criteria
The reporting of this systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement (16).Both English and Japanese observational studies and articles were eligible for inclusion.There were no limitations with regards to the date of publication of the included studies.Only articles for which the full-text versions could be retrieved were included.For a study to be suitable for the qualitative synthesis, it had to contain information on the patient's surgical treatment for CoCC.In addition, the study had to describe a defined follow-up period after the primary surgery, in which there had to be an assessment of the patient's outcome after the surgery.Any study, which did not meet the above-mentioned requirements, was not eligible for inclusion.

Literature search
A literature search was performed using the following terms: 'cholangiolocellular carcinoma' and

Study analysis
Survival rates were generated using the Kaplan-Meier method and compared by using the log-rank

Typical clinicopathological findings from our case presentation
The where the margin of the tumor was not clearly visible (Fig. 1b).Macroscopically, the resected tumor was whitish, solid, not encapsulated, and possessed an irregular margin (Fig. 1c).Histological findings obtained from the resected tumor showed small ductules, similar to proliferating cholangioles, in an anastomosing pattern along with abundant fibrous stroma (Fig. 1d).Immunohistochemically, the epithelial membrane antigen (EMA) was found to be strongly expressed in the membranous areas of the tubules.These findings are compatible with those obtained from other CoCC patients (Fig. 1e).

Literature review
We identified 23 articles in PubMed and 32 articles from other sources (Fig. 2) that contained suitable data for our study.Ultimately, 55 articles were previously treated in our clinic (Supplemental Table 1).The published diagnoses for all of the patients were true indications for surgical resection.

Clinicolpathological features of CoCCs
The clinicopathological characteristics of the examined CoCC cases are presented in Supplemental

Survival outcomes and recurrence patterns in patients with CoCCs
Survival outcome data was available for only 75 CoCC cases, including the patients from our hospital.

Subgroup analysis
By comparing the survival rates between the various subgroup identified by each predictive factor, the following factors were found to be significantly associated with poor outcomes after surgery:  1).

DISCUSSION
We conducted a retrospective analysis of 75 CoCC cases, with a focus on the clinicopathological features and surgical outcomes .This is the first report of CoCC on systematic review.CoCC is a rare type of malignant liver tumor.However, reports of CoCCs have been gradually increasing over the last decade, more likely due to its recognition by the WHO classification (13)

Figure 1 .
Figure 1.Typical clinicopathologic findings from our case presentation.(a) CT imaging showed high attenuating tumor with peripheral enhancement in early phase.Vessel penetratrion into the tumor showed in the early phase, no peripheral bile duct dilation.(b) The tumor had homogeneous enhancement on delayed phase whose margin of the tumor was not clear.(c) Macroscopically, the resected tumor was whitish color, solid, not encapsulated and had an irregular margin.(d) Histologic findings of the resected tumor showed small ductules similar to cholangioles proliferating in an anastomosing pattern with abundant fibrous stroma (HE, ×40).(e) Immunohistochemically, epithelial membrane antigen (EMA) was strongly positive in the membranous areas of the tubules.(EMA, ×40) radiological features of CoCCs have not been clarified because of their rarity and the inherent difficulties related to diagnosis.No specific features have been observed, except the lack of necrosis and a fibrous capsule and the presence of dual characteristics seen in both hepatocellular carcinomas and intrahapetic cholangiocarcinomas (2,5-7).However, imaging techniques have shown that CoCCs have some common features.For example, enhanced abdominal computed tomography (CT) imaging showed an enhancement of the tumor in the early phase (Fig. 1a), as well as homogeneous enhancement in the delayed phase,

Figure 2 .
Figure 2. PRISMA design showing selection of articles and patients cases for review.

Figure 3 .
Figure 3. Overall survival and disease-free survival in patients with CoCC of the liver.Kaplan-Meier estimates of overall survival (a) and Kaplan-Meier estimates of disease-free survival rates (b).
This study was subject to certain inherent limitations and biases associated with the small retrospective study design.A major limitation of our study was the uncertainly at which our results could be extrapolated, as the current study included case report and published pathological results, without performing the immunohistochemical staining for EMA.Immunohistochemical staining for EMA was performed 24 patients out of 75 patients in our study.Another potential limitation is the lack of reevaluation for the specimens by a dedicated pathologist.The establishment of a definite diagnosis for CoCC is inevitably pathological and therefore demands a professional who is highly specialized in liver disease.Because of their relatively recent discovery and extreme scarcity, the proper diagnosis of CoCCs is still challenging, even for high-volume liver pathologists.Therefore, to determine the best management strategy for CoCC and to improve the accuracy of prognosis, further collection and analysis of epidemiological and pathological data is necessary.In conclusion, pre-operative diagnosis of Cancer Research Frontiers.2016 Sept; 2(3): 396-410.doi: 10.17980/2016.396Review -404 -CoCCs would have been difficult, even with the various imaging modalities that are available.Currently, surgical treatment is the only curative management option for CoCCs.In patients with uncommon lesions in the liver, CoCCs should be considered a part of the differential diagnosis.

Table 1 .
Out of the 75 cases of CoCC, for which we (34)laying certain clinical symptoms.These symptoms were abdominal pain or discomfort in 8 patients, liver dysfunction in 1, and general fatigue in 1.Interestingly, among the CoCC patients, 33 (44.0%) were diagnosed with viral hepatitis.Out of the 75 patients, 11 were hepatitis B virus-positive, 19 were hepatitis C virus-positive, 3 were positive for both, and 31 patients were negative for both.at a single institute(34).Vascular invasion was observed in 10 out of the 21 (47.6%)patients, based on the evaluation of the resected specimens.

Table 1 .
The subgroup analysis of patients with CoCCs