Hepatolithiasis and intrahepatic cholangiocarcinoma: carcinogenesis based on molecular mechanisms

Hepatolithiasis is more frequently seen in East Asian countries than in Western countries, and it is well known to represent a high-risk state for intrahepatic cholangiocarcinoma. Intrahepatic cholangiocarcinoma is an aggressive tumor that shows a dismal outcome even after resection. Cancer results from multistep carcinogenesis; however, the precise molecular mechanisms involved in the genetic alterations in cancer remain unknown. The accumulation of alterations in cancer-related genes leads to disruptions in cell-cycle regulation and also to continuous cell proliferation. The present review provides an overview of cancer-related genes in intrahepatic cholangiocarcinogenesis arising in hepatolithiasis. Further study of molecular mechanisms in hepatolithiasis-related intrahepatic cholangiocarcinoma, and the delineation of the influence of the genes involved should lead to our understanding of cholangiocarcinogenesis.     

Macroscopic classification and preoperative diagnosis of intrahepatic cholangiocarcinoma in Japan

We reviewed the records of 64 patients with resected intrahepatic cholangiocarcinoma (ICC) according to the macroscopic classification proposed by the Liver Cancer Study Group of Japan, in which ICC is classified into three types based on the macroscopic appearance of the cut sur-face of the tumor: mass-forming, periductal-infiltrating, and intraductal growth types. There were 24 patients with the periductal-infiltrating type, 28 with the mass-forming type, and 12 with the intraductal growth type. The mass-forming type essentially showed expansive growth irrespective of hilar invasion. The periductal-infiltrating type of tumor exhibited diffuse infiltration along the portal pedicle, and preoperative planning of the resection procedure was similar to that for primary bile duct carcinoma of the hepatic confluence. Vascular resection and reconstruction was required in some patients with advanced disease. In the intraductal growth type of tumor, precise determination of tumor extent was difficult because of the ambiguity caused by abundant mucin secreted by the tumor and/or by the superficial mucosal spread of the tumor along the bile duct. Percutaneous transhepatic cholangioscopy provided the most reliable information for designing the operative procedure. The macroscopic classification is useful for preoperative diagnosis of tumor extent and for planning the surgical procedure.     

Clinical presentation,diagnosis and staging of cholangiocarcinoma

Cholangiocarcinoma (CCA) is a heterogeneous group of tumours, derived from cells of the biliary tree, which represent the second most frequent primary liver tumour. According to the most recent classifications, CCA can be subdivided into intrahepatic (iCCA) and extrahepatic (eCCA) which include perihilar (pCCA) and distal (dCCA) CCA. CCA are usually identified at advanced stages, when the primary tumour grows enough to produce a large liver mass or when jaundice has developed because of biliary tree obstruction. The ongoing challenges in the identification of risk factors and definition of a specific population at higher risk of developing CCA are the main challenges for the development of screening programs. Therefore, late diagnosis remains an unresolved issue in CCA. Imaging plays an important role in the detection and characterization of CCA, helping with radiological diagnosis, guiding biopsy procedures and allowing staging of the tumour. This review focuses on clinical presentations and diagnosis and staging techniques of CCA.     

Intrahepatic cholangiocarcinoma: macroscopic type and stage classification

The Liver Cancer Study Group of Japan established a classification of macroscopic type and the TNM staging of intrahepatic cholangiocarcinoma (ICC). With the observation of more than 240 resected cases of ICC, three fundamental types were established. They were: (1) mass-forming (MF) type, (2) periductal-infiltrating (PI) type, and (3) intraductal growth (IG) type. The MF type forms a definite mass, located in the liver parenchyma. The PI type is defined as ICC which extends mainly longitudinally along the bile duct, often resulting in dilatation of the peripheral bile duct. The IG type proliferates toward the lumen of the bile duct papillarily or like a tumor thrombus. The TNM classification of ICC was then designed, using 136 cases of the MF type resected curatively between 1990 and 1996 at member institutes. Univariate and multivariate analyses showed: (1) tumor 2?cm or less, (2) single nodule, and (3) no vascular and serous membrane invasion as prognostic factors. T factors were defined as follows: T1 is an ICC that meets all requirements of factors (1), (2), and (3); T2 meets two of the three requirements, T3 meets one of the three requirements and T4 meets none of the three requirements. Our data did not support the idea that the hepatoduodenal lymph node is regional. The N factors were defined as N0 no lymph node metastasis; and N1, positive at any nodes. Thus, the stages of ICC were defined as stage I, T1N0M0; stage II, T2N0M0; stage III, T3N0M0; stage IVA, T4N0M0 or any TN1M0; and stage IVB, any T any NM1.     

Anatomic and molecular pathology of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is the second most common malignant tumor of the liver, and ICC is reportedly increasing recently. ICC is usually adenocarcinoma with variable desmoplastic reaction, although there are several special or unusual histological features. ICC may arise at the large intrahepatic bile duct near the hepatic hilus and also from the bile ductules at the border of the hepatic parenchyma. On the anatomical level, the pathology of ICC differs depending on the region from which the ICC arises. At the large intrahepatic bile duct, ICC presents papillary growth and periductal infiltration. Some cases show extensive papillary growth and intraluminal spread with marked gastroenteric metaplasia. Mucus core protein 1 is expressed in aggressive ICC. ICC arising from ductules shares phenotypes of hepatocellular carcinoma. ICC in chronic biliary diseases, particularly arising in hepatolithiasis, presents precancerous lesions that include biliary epithelial dysplasia, as well as in-situ carcinoma. Chronic advanced hepatitis C is one of the background diseases of ICC. Chronic inflammation, with the upregulation of cyclooxygenase-2 and growth factors, and the formation of reactive oxygen species are one of the causative factors in the DNA damage of biliary epithelial cells. K-ras mutation and aberrant expression of p53 are found in one-third of ICCs. The latter may be due to mdm-2 upregulation. Hepatocyte growth factor/met and interleukin 6 (IL6)/IL6 receptor are involved in cell proliferation/mitoinhibition and apoptosis in ICC. Fibrous stroma formation and invasion involve the proliferation of Α-smooth muscle antigen-positive stromal cells, and cell-to-cell and cell-to-matrix interactions involving E-cadherin/catenin and CD44 and matrix proteinases may be involved in the invasion of ICC. Evasion of immune surveillance involving the Fas/FasL system is important in the malignant progression of ICC. Further molecular and genetic studies are mandatory to evaluate the pathogenesis and progression of ICC.     

Clinical experience in 126 patients with tissue-proved proximal cholangiocarcinoma

Abstract The diagnosis and treatment of 126 consecutive patients with tissue-proved cholangiocarcinoma which originates in or proximal to the common hepatic duct was reviewed. They are further divided into the hilar type and peripheral type tumours. The clinical presentations were commonly compatible with the hilar type tumour. However, the accurate pre-operative diagnosis of the peripheral type tumour was difficult because of the frequent association with hepatolithiasis (43.3%) and the high prevalence of hepatocellular carcinoma (HCC) in Taiwan; 25% of these patients underwent surgery for chronic cholangitis and 12.5% for HCC rather than cholangiocarcinoma. Among the 40 (31.7%) patients who had tumour resections, 24 were hilar type and 16 were peripheral type. There were no operative deaths and the mean survival time was 36.1 months (27.9 months for the hilar types, 52.2 months for the peripheral types). Sixty-three (50%) patients with hilar type tumours were only suitable for palliative procedures to relieve the jaundice. The 30-day mortality rate was 50 and 33.3% for the patients who received non-surgical and surgical drainages, but zero for the patients who had surgical bypasses. All the bypass patients experienced > 50% decrease of serum bilirubin, but this effect was obtained in less than half the patients receiving drainage procedures. Surgical resection significantly prolonged the survival (resection vs palliation vs no treatment = 36.1 vs 6.6 vs 3.6 months, P < 0.05), but no survival advantage was achieved in any of the palliative therapies. Five cases with tumour resection survived > 5 years. We conclude that surgical resection offers the best prognosis. For the majority of patients, however, a surgical bypass using cholangioenteric anastomosis achieved the most satisfactory palliation.     

Precancerous lesions of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC), also known as cholangiocellular carcinoma or peripheral bile duct carcinoma, is an intrahepatic malignant tumor that consists of cells resembling the biliary epithelium. The proportion of ICC among primary hepatic malignancies is approximately 10% worldwide. Although the etiology and pathogenesis remain unclear in a great majority of cases, preceding pathologic conditions or etiologies in the development of ICC are known or suspected in a proportion of these patients. Some forms of ICC, such as those associated with hepatolithiasis or liver fluke infestation, are endemic in parts of the world, particularly in East Asia. ICC is reportedly a late complication of primary sclerosing cholangitis. Most of these preceding pathologic conditions are forms of chronic cholangitis, and longstanding inflammation, chronic injury, and regenerative hyperplasia of the biliary epithelium may be causally related to malignant transformation. Biliary epithelial dysplasia is encountered in the intrahepatic bile ducts both near and remote from ICC foci in the liver and near and remote from the chronically inflamed biliary tree. This lesion could be a precancerous lesion, and it shows telomerase activity and increased proliferative activities. Furthermore, congenital and developmental disorders of the biliary system, such as Caroli's disease, congenital hepatic fibrosis, and pancreatico-biliary malformation are occasionally associated with ICC. Benign biliary tumors, such as biliary papillomatosis, may eventually undergo malignant transformation. These lesions could be regarded as precancerous or borderline lesions. Some ICCs may also develop in nonbiliary viral cirrhosis. In the majority of cases of ICC, however, the etiology, pathogenesis, and developmental processes and precancerous lesions of the ICC remain unclear.     

Guidelines for palliative surgery of cholangiocarcinoma

The aims of the guidelines are to help assess the evidence for palliation surgery in patients with cholangiocarcinoma (CCA). The guidelines are classified in accordance with the location of the primary lesion, i.e. intrahepatic, hilar, and distal. They are based on comprehensive literature surveys, including results from randomized controlled trials, systematic reviews and meta-analysis, and cohort, prospective, and retrospective studies. Intrahepatic CCA, i.e. resection of lymph-node-positive tumors and R1/R2 resections have not been shown to provide survival benefit: Evidence levels: 2b, 4; Recommendation grade C. Hilar CCA: R1 resection is justified as a very efficient palliation. Non-surgical biliary stenting is the first choice of palliative biliary drainage. Distal CCA: Resection of lymph-node-positive tumours and R1/R2 resections should be performed. Non-surgical stenting is regarded as the first choice of palliation for patients with short life expectancy. For patients with longer projected survival, surgical bypass should be considered. Palliative resections have a relevant beneficial impact on the outcome of patients with distal and hilar CCA. Non-surgical stenting is the first choice of palliative biliary drainage for patients with hilar CCA and for those with distal CCA and short life expectancy. For patients with distal CCA and longer projected survival, surgical bypass should be considered.     

Intrahepatic cholangiocarcinoma: current management and emerging therapies

Introduction: Intrahepatic cholangiocarcinoma (iCCA) is a malignancy with an increasing incidence and a high-case fatality. While surgery offers the best hope at long-term survival, only one-third of tumors are amenable to surgical resection at the time of the diagnosis. Unfortunately, conventional chemotherapy offers limited survival benefit in the management of unresectable or metastatic disease. Recent advances in understanding the molecular pathogenesis of iCCA and the use of next-generation sequencing techniques have provided a chance to identify ‘target-able’ molecular aberrations. These novel molecular therapies offer the promise to personalize therapy for patients with iCCA and, in turn, improve the outcomes of patients.

Area covered: We herein review the current management options for iCCA with a focus on defining both established and emerging therapies.

Expert commentary: Surgical resection remains as an only hope for cure in iCCA patients. However, frequently the diagnosis is delayed till advanced stages when surgery cannot be offered; signifying the urge for specific diagnostic tumor biomarkers and targeted therapies. New advances in genomic profiling have contributed to a better understanding of the landscape of molecular alterations in iCCA and offer hope for the development of novel diagnostic biomarkers and targeted therapies.     

Pathological classification of intrahepatic cholangiocarcinoma based on a new concept

Intrahepatic cholangiocarcinoma (ICC) arises from the lining epithelium and peribiliary glands of the intrahepatic biliary tree and shows variable cholangiocytic differentiation. To date, ICC was largely classified into adenocarcinoma and rare variants. Herein, we propose to subclassify the former, based on recent progress in the study of ICC including the gross classification and hepatic progenitor/stem cells and on the pathological similarities between biliary and pancreatic neoplasms. That is, ICC is classifiable into the conventional (bile duct) type, the bile ductular type, the intraductal neoplasm type and rare variants. The conventional type is further divided into the small duct type (peripheral type) and large bile duct type (perihilar type). The former is a tubular or micropapillary adenocarcinoma while the latter involves the intrahepatic large bile duct. Bile ductular type resembles proliferated bile ductules and shows a replacing growth of the hepatic parenchyma. Hepatic progenitor cell or stem cell phenotypes such as neural cell adhesion molecule expression are frequently expressed in the bile ductular type. Intraductal type includes papillary and tubular neoplasms of the bile duct (IPNBs and ITNBs) and a superficial spreading type. IPNB and ITNB show a spectrum from a preneoplastic borderline lesion to carcinoma and may have pancreatic counterparts. At invasive sites, IPNB is associated with the conventional bile duct ICC and mucinous carcinoma. Biliary mucinous cystic neoplasm with ovarian-like stroma in its wall is different from IPNB, particularly IPNB showing cystic dilatation of the affected ducts. Rare variants of ICC include squamous/adenosquamous cell carcinoma, mucinous/signet ring cell carcinoma, clear cell type, undifferentiated type, neuroendocrine carcinoma and so on. This classification of ICC may open up a new field of research of ICC and contribute to the clinical approach to ICC.     

影像学表现为肝内胆管细胞癌的双表型肝细胞癌1例报告

1病例资料患者男性,63岁,因体检发现上腹部肝左叶占位,考虑恶性肿瘤,于2018年10月23日收入南通大学附属医院肝胆外科。患者自诉有慢性HBV病史30余年,未正规治疗,否认家族性肝癌病史。查体:全腹未及肿块,肝区无叩痛,肝脾肋下未触及。肿瘤指标:癌胚抗原16.7 ng/ml,血清铁蛋白>2000 ng/ml,CA19-97289.8 U/ml,AFP 3.57 ng/ml,CA72-41.10 U/ml。异常凝血酶原(PIVKA-Ⅱ)46.00 mAU/ml。HBV核酸定量<1000拷贝/ml。HBsAg阳性(48.80 ng/ml),抗-HBe阳性(>6.00 PEIU/ml),抗-HBc阳性(6.52 PEIU/ml)。胸苷激酶1测定:细胞质胸苷激酶0.49 PM。上腹部增强CT示:肝占位,考虑肝内胆管细胞癌(图1)。     

Autoimmune cholangitis and cholangiocarcinoma

Autoimmune cholangitis, immunoglobulin G4‐associated cholangitis (IAC), is a part of multiorgan IgG4‐related systemic disease, which was recognized as a new clinicopathological entity in recent years. IAC is defined as a biliary stricture that responds to steroid therapy, frequently is associated with other fibrosing conditions, especially autoimmune pancreatitis and is characterized by elevation of IgG4 in serum and infiltration of IgG4 positive plasma cells in bile ducts. Since IAC shares a number of clinical, biochemical, and imaging features with cholangiocarcinoma (CCA), it is often misdiagnosed as CCA, and unnecessary surgery was performed. In this compact review, we clarify the disease of IAC, summarize criteria for diagnosis of IAC, discuss the role of CA 19‐9, and provide key information to differentiate diagnosis of IAC from CCA. IAC should be highly suspected in unexplained biliary stricture associated with increased IgG4 (in serum especially in bile) and other organ involvement (kidney, retroperitoneum etc. especially pancreas in which there are abundant IgG4‐positive plasmocytes infiltration). Correct diagnosis of IAC will avoid unnecessary surgery because IAC responds well to steroid therapy. In a word, increased IgG4 levels, other organ involvement and response to steroids are keys to distinguishing IAC from CCA.     

A high-risk signature for patients with multiple myeloma established from the molecular classification of human myeloma cell lines

Background

Multiple myeloma is a plasma-cell tumor with heterogeneity in molecular abnormalities and treatment response.

Design and Methods

We have assessed whether human myeloma cell lines have kept patients’ heterogeneity using Affymetrix gene expression profiling of 40 human myeloma cell lines obtained with or without IL6 addition and could provide a signature for stratification of patient risk.

Results

Human myeloma cell lines, especially those derived in the presence of IL6, displayed a heterogeneity that overlaps that of the patients with multiple myeloma. Human myeloma cell lines segregated into 6 groups marked by overexpression of MAF, MMSET, CCND1, FRZB with or without overexpression of cancer testis antigens (CTA). Cell lines of CTA/MAF and MAF groups have a translocation involving C-MAF or MAFB, cell lines of groups CCND1-1 and CCND1-2like have a t(11;14) and cell lines of group MMSET have a t(4;14). The CTA/FRZB group comprises cell lines that had no or no recurrent 14q32 translocation. Expression of 248 genes accounted for human myeloma cell line molecular heterogeneity. Human myeloma cell line heterogeneity genes comprise genes with prognostic value for survival of patients making it possible to build a powerful prognostic score involving a total of 13 genes.

Conclusions

Human myeloma cell lines derived in the presence of IL6 recapitulate the molecular diversity of multiple myeloma that made it possible to design, using human myeloma cell line heterogeneity genes, a high-risk signature for patients at diagnosis. We propose this classification to be used when addressing the physiopathology of multiple myeloma with human myeloma cell lines.     

Radiation therapy, chemotherapy and chemoradiation in hilar cholangiocarcinoma

Background. Hilar cholangiocarcinoma is a rare tumour which is best managed by an aggressive surgical approach. The role of adjuvant or neoadjuvant radiation therapy, chemotherapy or chemoradiation remains controversial, as no prospective randomized studies have been performed. Methods. This review summarizes the recent literature regarding the role of radiation, chemotherapy and chemoradiation in hilar cholangiocarcinoma. The results of a biliary cancer questionnaire regarding current treatment strategies are also reported. Results. A number of retrospective studies have shown that patients treated with adjuvant radiation therapy have prolonged survival compared with untreated patients. However, most of these reports did not control for tumour stage or performance status. A carefully controlled trial from the Johns Hopkins Hospital did not demonstrate any benefit for adjuvant radiation therapy. A number of phase II trials of chemotherapy have demonstrated modest response rates (20–40%). The best responses have been reported with 5-fluorouracil (5-FU) in combination with interferon-alpha or with leucovorin and mitomycin C. Recent non-randomized reports of chemoradiation with 5-FU with or without gemcitabine as the radiosensitizer suggest, but do not prove, improved survival. Adjuvant chemoradiation is currently being employed at specialized centres most often in the Americas (71%) and the Asia/Pacific region (55%) and to a lesser degree in Europe (29%). Discussion. The only chance for long-term survival in patients with hilar cholangiocarcinoma is complete resection with negative margins. Neither radiation therapy nor chemotherapy alone has been proven to prolong survival in completely or partially resected patients or in unresected patients. Recent uncontrolled data suggest that chemoradiation may improve survival in resected and locally unresectable patients. However, prospective, randomized multicentre trials need to be performed to confirm efficacy.     

Pathology of combined hepatocellular‐cholangiocarcinoma

Combined hepatocellular‐cholangiocarcinoma is a rare primary neoplasm in the liver. It has gained increasing recognition recently, which in part may be due to more extensive sampling of the explants and surgical resection specimens, the diagnostic challenges encountered in the clinical practice, and the yet to be determined clinical outcome, but partly may be attributed to its intriguing histogenesis/cells of origin. This review aims to update combined hepatocellular‐cholangiocarcinoma with an emphasis on the pathological diagnosis, including the differential diagnosis and its diagnostic pitfalls, the possible cell of origin of this neoplasm, and its clinical outcome.     

Experimental models to unravel the molecular pathogenesis,cell of origin and stem cell properties of cholangiocarcinoma

Human cholangiocarcinoma (CCA) is an aggressive tumour entity arising from the biliary tree, whose molecular pathogenesis remains largely undeciphered. Over the last decade, the advent of high‐throughput and cell‐based techniques has significantly increased our knowledge on the molecular mechanisms underlying this disease while, at the same time, unravelling CCA complexity. In particular, it becomes clear that CCA displays pronounced inter‐ and intratumoural heterogeneity, which is presumably the consequence of the interplay between distinct tissues and cells of origin, the underlying diseases, and the associated molecular alterations. To better characterize these events and to design novel and more effective therapeutic strategies, a number of CCA experimental and preclinical models have been developed and are currently generated. This review summarizes the current knowledge and understanding of these models, critically underlining their translational usefulness and limitations. Furthermore, this review aims to provide a comprehensive overview on cells of origin, cancers stem cells and their dynamic interplay within CCA tissue.