Cholangiocarcinoma: Expanding the Spectrum of Risk Factors

Introduction

Cholangiocarcinoma (CCA) is an epithelial cancer originating from the bile ducts with features of cholangiocyte differentiation. The global incidence of this rare disease is on the rise, and it is the second most common primary hepatobiliary malignancy. We reviewed risk factors for cholangiocarcinoma development and also described potential screening strategies for this malignancy. We also report two cases in which CCA developed in patients without previously determined risk factors known for CCA.

Discussion

The first case is a patient with longstanding secondary sclerosing cholangitis (SSC), and the second is a patient with autoimmune hepatitis (AIH). These two cases may indicate a possible association between SSC and AIH with CCA, thus, expanding the spectrum of risk factors of CCA.     

Ulcerative colitis-associated colorectal cancer arises in a field of short telomeres, senescence, and inflammation

Inflammation plays a role in the progression to cancer and it is linked to the presence of senescent cells. Ulcerative colitis (UC) is a chronic inflammatory disease that predisposes to colorectal cancer. Tumorigenesis in this setting is associated with telomere shortening that can be observed in the nondysplastic epithelium of UC patients with high-grade dysplasia (HGD) or cancer (UC progressors). We hypothesized that a preneoplastic field of inflammation, telomere shortening, and senescence underlies tumor progression in UC progressors. Multiple biopsies of varying histologic grade were collected along the colon of nine UC progressors and analyzed for telomere length, DNA damage, senescence, p53, p16, and chronic and acute inflammation. Twenty biopsies from four UC nonprogressors and twenty-one biopsies from control individuals without UC were also analyzed. Short telomeres and increased DNA damage, senescence, and infiltrating leukocytes were observed in biopsies located less than 10 cm from HGD or cancer. Low-grade dysplasia (LGD) had the shortest telomeres along with the highest levels of senescence and infiltrating leukocytes, whereas HGD biopsies showed the opposite pattern. The expression of p16 and p53 was low in nondysplastic biopsies but progressively increased in LGD and HGD. In addition, high levels of infiltrating leukocytes were associated with telomere shortening, senescence, and reduced p53 expression. These results suggest that dysplasia arises in a preneoplastic field of chronic inflammation, which leads to telomere shortening, DNA damage, and senescence. Our findings argue that senescence acts as a tumor suppressor mechanism that is abrogated during the transition from LGD to HGD in UC.     

Estimating cumulative risks for breast cancer for carriers of variants in uncommon genes

The rapid clinical embrace of next generation multigene cancer predisposition panels has resulted in discovery of DNA variants in genes for which very limited data on penetrance has been published. Evidence for increased risks associated with these genes is often expressed in odds ratios and studies often were conducted on a priori high risk cohorts, i.e. those with young onset disease and/or positive family histories. Despite these limitations, one can estimate cumulative risks, which may be useful for health care providers who are counselling individuals on their results. We present cumulative risks for several under-studied genes and provide generic information that can be extrapolated to data still emerging.     

Cancer risk in primary sclerosing cholangitis: Epidemiology,prevention, and surveillance strategies

Primary sclerosing cholangitis(PSC) is a rare cholestatic liver disease characterized by progressive fibroinflammatory destruction of the intra-and/or extrahepatic biliary ducts. While its features and disease course can be variable,most patients with PSC have concurrent inflammatory bowel disease and will eventually develop liver cirrhosis and end-stage liver disease, with liver transplantation representing the only potentially curative option. Importantly,PSC is associated with a significantly increased risk of malignancy compared to the general population, mainly cholangiocarcinoma, gallbladder carcinoma,hepatocellular carcinoma, and colorectal cancer, with nearly 50% of deaths in patients with PSC being due to cancer. Therefore, robust surveillance strategies are needed, though uncertainty remains regarding how to best do so. In this review, we discuss the epidemiology, prevention, and surveillance of cancers in patients with PSC. Where evidence is limited, we present pragmatic approaches based on currently available data and expert opinion.     

Cerebrovascular consequences of pseudohyperaldosteronism

J Clin Hypertens (Greenwich). 2012;00:00–00. ©2012 Wiley Periodicals, Inc. The study of mechanistically defined forms of hypertension may provide insight into the relationship between hypertension and stroke. The author retrospectively studied a cohort of 23 individuals with pseudohyperaldosteronism (PHA), a condition associated with pathologic activation of the distal nephron epithelial sodium channel but low renin and aldosterone levels. During a median follow‐up of 11 years (range: 1–30), 4 of 23 (17.4%) patients had a cerebrovascular event recorded. Intracranial hemorrhage was not observed in any patient. Cerebrovascular events tended to occur in older patients, minorities, and patients with a later diagnosis of PHA and additional vascular risk factors. In addition to strict blood pressure control, patients with PHA should have early evaluation and treatment of other vascular risk factors to reduce the risk of stroke.     

Old and new treatments for primary biliary cholangitis

Primary biliary cholangitis (formerly primary biliary cirrhosis) is a rare progressive cholestatic liver disease, whose hallmark features include a persistently elevated alkaline phosphatase level, presence of anti‐mitochondrial antibodies and characteristic histology. Since 1998, ursodeoxycholic acid (UDCA), a bile acid, has been the only available therapeutic agent. Primary biliary cholangitis is associated with the development of end‐stage liver disease, increased morbidity and mortality. UDCA has been shown to improve serum biochemistries, histology and delay the need for liver transplantation. The clinical issue is that approximately 25%‐40% of patients do not respond to this standard therapy. In recent years, many trials have investigated alternative and adjunctive treatments, leading to the recent approval of obeticholic acid, an analogue of chenodeoxycholic acid, which has shown significant and sustained reductions in alkaline phosphatase levels in combination with UDCA. Obeticholic acid has rapidly been embraced as a new agent to improve the biochemical profile in refractory patients, in addition to being approved for use as monotherapy in patients who cannot tolerate UDCA. There are several other studies and targets which are being investigated. This review is intended to highlight the benefits of UDCA, educate the reader on the newly available obeticholic acid, and to summarize the many ongoing trials and therapeutic targets being investigated in attempts to control and cure primary biliary cholangitis.     

An update on cancer risk and surveillance in primary sclerosing cholangitis

Malignancy represents substantial morbidity and mortality in patients with primary sclerosing cholangitis (PSC). This subset of patients has been proven to be at increased risk for developing cholangiocarcinoma, gallbladder carcinoma and colorectal cancer in those with overlapping inflammatory bowel disease. Herein, we review the prevalence of these malignancies and recommend screening tools and current knowledge to reduce the disease burden in this population. Cholangiocarcinoma is the most dominant malignancy affecting PSC patients, with a lifetime risk ranging from 5% to 20%. We advocate for serial US or MRI/MRCP and CA 19‐9 to screen for cholangiocarcinoma. Gallbladder cancer has a lifetime risk around 2% in this population and we agree with annual imaging for lesions as recommended by national guidelines. Patients with PSC and concomitant IBD are at increased risk of colorectal carcinoma from time of diagnosis and therefore should likely undergo annual surveillance. The low rates of hepatocellular cancer and pancreatic cancer indicate surveillance for these malignancies is less advantageous.     

Primary biliary cirrhosis

Opinion statement  

Survival after inflammatory bowel disease-associated colorectal cancer in the Colon Cancer Family Registry

AIM: To investigate the survival of individuals with colorectal cancer (CRC) with inflammatory bowel disease (IBD-associated CRC) compared to that of individuals without IBD diagnosed with CRC. METHODS: Epidemiologic, clinical, and follow-up data were obtained from the Colon Cancer Family Registry (Colon CFR). IBD-associated cases were identified from self-report of physician diagnosis. For a subset of participants, medical records were examined to confirm self-report of IBD. Cox proportional hazards regression was applied to estimate adjusted hazard ratios (aHR) and 95%CI of mortality, comparing IBD-associated to non-IBD-associated CRC, adjusted for age at CRC diagnosis, sex, Colon CFR phase, and number of prior endoscopies. Following imputation to complete CRC stage information, adjustment for CRC stage was examined. RESULTS: A total of 7202 CRC cases, including 250 cases of IBD-associated CRC, were analyzed. Over a twelve year follow-up period following CRC diagnosis, 2013 and 74 deaths occurred among non-IBD associated CRC and IBD-associated CRC patients, respectively. The difference in survival between IBD-associated and non-IBD CRC cases was not statistically significant (aHR = 1.08; 95%CI: 0.85-1.36). However, the assumption of proportional hazards necessary for valid inference from Cox regression was not met over the entire follow-up period, and we therefore limited analyses to within five years after CRC diagnosis when the assumption of proportional hazards was met. Over this period, there was evidence of worse prognosis for IBD-associated CRC (aHR = 1.36; 95%CI: 1.05-1.76). Results were similar when adjusted for CRC stage, or restricted to IBD confirmed in medical records. CONCLUSION: These results support the hypothesis that IBD-associated CRC has a worse prognosis than non-IBD-associated CRC.