Cholangiocarcinoma

Cholangiocarcinoma is a highly malignant disease, originating from the ductular epithelia of the extrahepatic and intrahepatic biliary apparatus. Unfortunately, the incidence of this aggressive malignancy is increasing in western societies. Both diagnosis and management are complex and difficult. Moreover, there are a plethora of diagnostic and management approaches depending on the context of the disease. Therefore, this issue of Seminars in Liver Disease. devoted to the topic of cholangiocarcinoma, is both timely and topical.

In the first article, Shaib and El-Serag review the epidemiology of cholangiocarcinoma. This is a wonderful contribution, highlighting in detail the increasing incidence of this malignancy in western cultures. Risk factors, especially the occurrence of primary sclerosing cholangitis and other inflammatory conditions of the biliary tree, are discussed in detail. Unfortunately, there does not appear to be any epidemiological information that would suggest which patients with primary sclerosing cholangitis are at either high or low risk for the development of this malignancy. This remains a problematic clinical dilemma in a hepatologic practice. This contribution sets the background for the remainder of this issue, which deals with diagnostic and management problems.

In the second article, Berthiaume and Wands review the molecular pathogenesis of cholangiocarcinoma. Well-established cancers in general must develop autonomous proliferating signals, inhibit apoptosis, and develop mechanisms to ensure adequate nutrient supply. The latter phenomenon primarily occurs via angiogenesis. The authors describe in detail the mechanisms by which cholangiocarcinoma cells initiate autonomous signaling pathways and evade apoptosis. Classic pathways relevant to this malignancy that initiate angiogenesis are reviewed. The authors also highlight a novel protein, which appears to be upregulated only by cholangiocarcinomas: human aspartyl (asparaginyl) beta-hydroxylase. This protein appears to be important in cell migration, motility, and likely metastases. Moreover, it is a surface protein and unique antibodies can be targeted to this protein. These unique antibodies may ultimately prove to have therapeutic value in the treatment of this cancer. The elucidation of these molecular pathways opens a wide variety of potential diagnostic and screening strategies aimed toward earlier diagnosis when surgery may be more efficacious and may also provide a multitude of molecular targets for future therapeutic approaches.

Cholangiocarcinomas are relatively acellular, highly desmoplastic cancers that are difficult to diagnose confidently. In an evidence-based approach, Nehls, Gregor, and Klump review the usefulness of a variety of serum and bile markers for cholangiocarcinoma. In the era of proteomics and genomics, this is a particularly useful contribution to this issue of Seminars in Liver Disease. In a very comprehensive and impressively thorough manner, the authors review all of the serum markers that have been studied in this disease. Serum signaling CA 19-9 values have the greatest use in this disease, although the ability to detect early lesions is unclear. The role of detecting epigenetic or genetic lesions, or both, in bile is also thoroughly reviewed. Of the genes involved in the genesis of cholangiocarcinoma, the P16INK4A appears to be an important locus in the genesis of, and therefore in the diagnosis of, this cancer. P16 loss of heterozygosity or promoter hypermethylation, or both, is common in this malignancy, and they have both been used as diagnostic tools. Finally, the authors review the role of cytological techniques such as digital image analysis and fluorescent in situ hybridization for detecting this malignancy. The authors conclude that cytological techniques evaluating DNA aneuploidy are extremely promising for detecting early cholangiocarcinoma. Such techniques are now being rapidly established at a variety of institutions and should greatly aid in our diagnostic armamentarium for this difficult to diagnosis cancer.

Manfredi and colleagues review the role of magnetic resonance (MR) imaging for diagnosing and staging this cancer. Cholangiocarcinomas are difficult to visualize, and surgical approaches need to take into consideration the relationship of the tumor to the two lobes of the liver, involvement or lack of involvement of secondary biliary radicals, and encasement of vessels and extrahepatic and intrahepatic metastases. In the past, staging of cholangiocarcinoma was difficult and required multiple imaging modalities. However, MR imaging has apparently supplanted this approach because of the availability of MR cross-sectional imaging, MR cholangiograms and MR angiography. Thus, in many instances, MR imaging appears to be able to stage the disease with one imaging modality. This is a significant advance, and the authors point out the strengths and weaknesses of MR imaging for the diagnosis and staging of this cancer.

Cholangiocarcinoma often presents with bile duct obstruction. Indeed the cholestasis contributes to the morbidity and mortality of this disease. Therefore, endoscopic stenting of biliary obstruction is an important tool in the management of this disease. Abu-Hamda and Baron extensively review current concepts in regard to stenting these lesions. The indications for metallic versus plastic stenting are discussed. The authors discuss bilateral versus unilateral stenting for optimal relief of biliary obstruction. This article will be of great practical value to endoscopists, physicians, and surgeons working with endoscopists in the management of these patients.

Recently, photodynamic therapy has emerged as a potential therapeutic modality for the treatment of cholangiocarcinoma. Photodynamic therapy consists of the administration of a photosensitizing agent followed by the administration of light of the appropriate wavelength to the tumor. Photosensitizers accumulate preferentially in a tumor, allowing selective photodamage to the cancer. Very recently a randomized controlled trial of photodynamic therapy versus endoscopic stenting has been performed, demonstrating a survival benefit in those patients receiving photodynamic therapy. Berr reviews the rationale, goals, and objectives of photodynamic therapy in the management of these patients. A variety of detailed pragmatic issues are discussed that should allow individuals and institutions wishing to implement this therapy to do so. Photodynamic therapy is an emerging and novel treatment in the management of cholangiocarcinoma that warrants more widespread application.

Surgical treatment of cholangiocarcinoma has been the mainstay for the definitive treatment of this disease. Jarnagin and Shoup review and discuss the surgical management of cholangiocarcinoma. Indications and staging systems are reviewed. The extensive database for cholangiocarcinoma in the Memorial Sloan-Kettering system is used to provide outcome data as a function of stage. A novel preoperative staging system developed by the authors has been proposed. This article will help nonsurgeons understand which patients are candidates for surgery and the limitations of surgery in the treatment and management of this disease.

In the final article of this issue Seminars in Liver Disease, Heimbach and associates review and discuss the benefits of a complex, multidisciplinary approach to the management of highly selected patients with cholangiocarcinoma. These patients, who have limited but unresectable disease, undergo preoperative chemoirradiation followed by liver transplantation as definitive management for the disease. This group at the Mayo Clinic has been pioneering this approach since 1994. This is the most up-to-date and detailed discussion of their experience. The toxicities, drop-out rates, and excellent outcome data are provided in detail. This article is extremely useful for determining which patients should be referred for potential transplantation with this disorder and should help other transplant centers implement this protocol if they so desire.

In summary, a variety of novel and emerging diagnostic and management approaches for patients with cholangiocarcinoma are provided in this issue of Seminars in Liver Disease. Given the increasing prevalence of this disease in western societies, this issue should have an impact on the care and management of this difficult problem. This issue should be of interest not only to clinicians and surgeons but also to basic scientists. Additional diagnostic and therapy modalities are needed, and hopefully this state-of-the-art information will help provide a foundation for further improvements.