Fast Facts: Cholangiocarcinoma: Diagnostic and therapeutic advances are improving outcomes

By R.T. Shroff and C. Braconi

Cholangiocarcinomas (CCAs) are a group of heterogeneous tumors that have traditionally had poor prognosis. Despite being rare, the global incidence of CCA has increased dramatically over the last few decades. However, alongside this, there have been advancements in our understanding, diagnosis and treatment, improving the overall survival and quality of life of patients with advanced disease. This compact yet comprehensive review of CCA serves as a guide for physicians, oncologists, allied health professionals, scientists, patients and caregivers to update their knowledge of the most recent clinical developments and most promising areas of research. Table of Contents: • Pathophysiology, etiology and epidemiology • Diagnosis • Biliary drainage and supportive care • Surgical resection and transplantation • Translational research • Systemic therapy • Immunotherapy • Radiotherapy and photodynamic therapy

• Language: English
• Publisher: S. Karger
• Release date: Apr 8, 2021
• ISBN: 9783318068108

Book preview

Introduction

Cholangiocarcinomas (CCAs) are a group of heterogeneous tumors that have traditionally had poor prognosis. Despite CCA being rare, its global incidence has increased dramatically over the last few decades. In turn, the oncology community’s engagement with patients with CCA has grown over the last 10 years as a consequence of increased epidemiological data, improved diagnostic technologies and greater awareness.

Advancements in our understanding of biology and the characterization of the genomic landscape of CCA have led to the development of novel therapeutics and positive progress in clinical management. The adoption of updated coding and classification systems, approval of novel therapies and identification of molecular features have opened up the possibility of personalized oncology.

Over the last decade, targeted agents have improved the overall survival and quality of life of patients with advanced disease. Some of these agents may emerge as chemotherapy-free first-line options. New cytotoxic treatments are also under investigation for patients who lack targetable alterations; ongoing studies of immunotherapy have shown benefits in selected populations, warranting further investigation into optimal patient selection strategies and efficacy. Advances in adjuvant and neoadjuvant therapies, as well as surgical and radiation techniques, have also resulted in clinically meaningful benefits. Nonetheless, a number of unmet needs continue to pose challenges to the research community. These include the development of plans for early diagnosis, the identification of biomarkers of chemotherapy sensitivity, strategies to overcome drug resistance, the establishment of preclinical models to boost scientific discoveries and the individualization of treatment.

This compact yet comprehensive review of CCA serves as a guide for physicians, oncologists, allied health professionals, scientists, patients and caregivers to update their knowledge of the most recent clinical developments and most promising areas of research. With many novel therapeutics and combination therapies on the horizon, the coming decade will surely bring pivotal advancements in the treatment and management of CCA.

1Pathophysiology, etiology and epidemiology

Pathophysiology

CCAs are a heterogeneous group of malignancies that arise from the epithelium of the biliary tract,¹ which consists of intra- and extrahepatic bile ducts.

Bile drains from the gallbladder into the extrahepatic bile duct through the cystic duct for transport to the duodenum. The left and right hepatic ducts (and their first three branches) are referred to as the hilar and perihilar bile ducts.²,³ They are grossly visible and are also known as large intrahepatic bile ducts. The remaining bile ducts within the liver parenchyma that are proximal to the left and right hepatic ducts are referred to as small intrahepatic bile ducts. Together with glandular structures they form the complex biliary drainage network (Figure 1.1).¹–⁴

Classification. CCAs are classified based on their anatomic location.³ Intrahepatic CCAs (iCCAs) arise from ductal epithelium within the liver parenchyma, while extrahepatic CCAs (eCCAs) are divided into perihilar CCAs (pCCAs, previously known as Klatskin tumors), which arise at the junction between second-order bile ducts and the cystic duct, and distal CCAs (dCCAs), which arise in the region between the cystic duct and the ampulla of Vater.³,⁵–⁷ It is increasingly evident that these tumors have a great degree of inter- and intratumor heterogeneity, which has important implications for patient treatment and prognosis.

Histological subtypes. The majority of CCAs are adenocarcinomas. Histologically, iCCAs have features of acini, papillary and tubular structures and are further subclassified into small- and large-bile duct types based on their anatomic cells of origin.²,³,⁸,⁹

The small-bile duct subtype is characterized by epithelial cells of columnar to cuboidal morphology, with nodular growth patterns and infiltration into the liver parenchyma. These tumors are typically well or moderately differentiated. Poorly differentiated CCAs have more cribiform growth with nuclear and cellular pleomorphism.

Figure 1.1 Anatomic locations of CCAs.

The large-bile duct subtype is characterized by flat, papillary structures with luminal spread. Other histological variants include squamous cell carcinoma, which features keratinization and is typically well differentiated,²,³ and adenosquamous cell carcinoma, which contains features of adenocarcinoma and squamous cell carcinoma intermixed or isolated within the tumor. The mucinous subtype is characterized by carcinoma cells within regions of mucin and sometimes has signet ring cell features.

Other histological subtypes include clear cell, lymphoepithelioma-like, neuroendocrine, sarcomatous and anaplastic types. Cytokeratins 7 and 19 and epithelial membrane antigen are immunohistochemical markers of CCA (Figure 1.2). Detailed reviews of CCA histology can be found elsewhere.²,³,⁸,⁹

Molecular subtypes. Multiple targetable genetic alterations have been identified in CCAs and several molecular profiling studies have been conducted using different targeted and whole-exome sequencing platforms.⁹,¹¹–¹⁷

Figure 1.2 Cholangiocarcinoma biopsy with staining. (a) Hematoxylin and eosin staining; scale bars are in μm. Reproduced, under a Creative Commons CC-BY license, from Lampis et al. 2018.¹⁰ (b) Immunohistochemical staining for cytokeratin 19 at ×20 and ×40 magnifications; reproduced courtesy of Dr Dongguang Wei and Dr Dongfeng Tan (Department of Pathology, University of Texas MD Anderson Cancer Center).

Comprehensive molecular profiling of 554 CCAs, which included 412 iCCAs and 57 eCCAs, identified p53, CDKN2A/B, KRAS, ARID1A, IDH1 and FGFR alterations as commonly occurring in iCCA.¹¹ KRAS, p53, CDKN2A/B and SMAD4 were frequently altered in the eCCA cohort. Whole-exome sequencing of 38 CCA specimens, the majority of which were from patients with iCCA who were naive to systemic treatment and radiotherapy, identified 2831 somatic mutations, 66% (1869) of which were coding alterations.¹⁵ A median mutation rate of 1.38 per Mb was identified, categorizing CCA in the intermediate range according to The Cancer Genome Atlas analysis of mutation rate.

From this and multiple other studies, common recurring genetic alterations have been identified in the tumor suppressor genes p53, ARID1A/B, BAP1, STK11 and PTEN, and in the oncogenes KRAS, BRAF, PIK3CA and IDH1/2.⁹,¹¹–¹⁷ Several