Research ArticleRising trends in cholangiocarcinoma: Is the ICD classification system misleading us?
Introduction
Cholangiocarcinoma (CC) is the commonest and most lethal malignancy of the biliary tract. CC are divided into intrahepatic (IHCC), which arise in the liver parenchyma, and extrahepatic (EHCC), arising in the biliary tract outside the liver. Intrahepatic cholangiocarcinoma (IHCC) is the second most common primary hepatic malignancy worldwide, after hepatocellular carcinoma [1]. CC arising at the liver hilum (hilar CC) are anatomically defined as a subset of EHCC, since the bifurcation of the hepatic ducts lies outside the liver parenchyma. IHCC are conventionally documented to account for 5–10% of all CC cases; hilar CC for 60–70%; and EHCC for 15–20% [2], [3], [4]. The eponym ‘Klatskin’ tumour has been adopted for hilar CC, particularly in the USA, after the American hepatologist who first described the unique features of these tumours in 1965 [4]. The terms ‘hilar’ and ‘Klatskin’ are interchangeable.
IHCC, hilar, and EHCC have distinct clinical and morphological features and often require different approaches to management [2], [3], [4]. Previous studies from England and Wales have shown that age-standardised mortality rates per 100,000 population for intrahepatic bile duct tumours (IHBD) increased markedly over a 30-year period since 1968, from 0.10 to 1.49 in men and 0.05 to 1.24 in women [5]. There was a 15-fold increase in age-specific mortality rates in those aged 45 years and above; and since 1993, tumours of the IHBD are the commonest recorded cause of primary liver tumour-related death in England and Wales [5]. Age-standardised incidence rates (ASIR) for IHBD cancers increased concomitantly, approximately 12-fold [6]. These studies showed an accompanying fall in mortality and incidence rates for extrahepatic bile duct tumours (EHBD) [5], [6]. Recently, a number of international studies have reported increasing mortality and incidence rates for IHBD and decreasing rates for EHBD, over the last few decades [7], [8], [9], [10], [11], [12]. In contrast, a recent study of Danish Cancer Registry data between 1978 and 2002 showed a fall in incidence rates of both IHBD (1.27–0.46 per 100,000 population) and EHBD (1.05–0.74). This occurred across all age groups and in both sexes [13]. A recent study of a well defined French population in Burgundy reported a fall in age-standardised incidence rates for intrahepatic biliary tract cancer between 1976–1980 and 2001–2005, from 0.3 to 0.2/100,000 population [14].
The reasons for these dynamic trends in different sub-groups of CC are unclear. Why IHBD is reportedly increasing in most countries but not in others is unknown. The trends may reflect genuine changes in the incidence of these tumours. However, given the complexity over how CC are classified and several revisions of the International Classification of Diseases (ICD) coding system for liver and biliary tract tumours over the past three decades, with each revision being adopted by different countries at different times, trends in CC rates could theoretically be influenced by coding misclassification. This is particularly likely if hilar/’Klatskin’ tumours, which account for the majority of CC and are in fact extrahepatic, are misclassified as intrahepatic tumours. To date, only one published study has examined this issue [15]. This US investigation examined the impact of classification of ‘Klatskin’ CC on IHCC and EHCC incidence rates using data from the Surveillance, Epidemiology and End Results (SEER) cancer registry program of the US National Cancer Institute (NCI) [15]. Studying data from 1992 to 2000, before ICD-O-3 was introduced, the investigators found that 91% of the ‘Klatskin’ CC reported between 1992 and 2000 were incorrectly coded as IHCC, rather than EHCC, resulting in an overestimation of IHCC incidence by 13% and a similar underestimation of EHCC incidence. They also found a lower than expected proportion of ‘Klatskin’ tumours in the SEER dataset (8%). This remains unexplained. No similar studies have been done elsewhere and no previous study has directly questioned cancer registries as to how they code different sub-groups of bile duct tumours.
The aims of our study were to:
- (1)
analyse incidence trends in IHBD and EHBD tumours in relation to changes in ICD-O classification, and to investigate the impact of potential misclassification of hilar/’Klatskin’ tumours on site-specific incidence rates for bile duct tumours in England and Wales and the US.
- (2)
investigate whether coding practices by cancer registries in England and Wales could affect reported rates of sub-groups of CC.
Section snippets
Materials and methods
According to the World Health Organisation’s (WHO) bi-axial International Classification of Diseases for Oncology (ICD-O), CC are classified as intra- or extrahepatic. The ICD-O was introduced in 1979 and assigns two codes dependent upon the tumour’s anatomical topography and morphology (based on histology) [16]. Topography codes are defined in the neoplasm section of the ICD, and are applicable to all tumours, regardless of whether their growth behaviour is malignant, benign, in situ or
Total number of cases
Between 1990 and 2008 in England and Wales, the total number of cases reported as IHBD (C22.1) rose from 226 to 1311 (Table 1A). Male cases increased from 116 to 639, and females from 110 to 672. In the same period, the number of cases reported as EHBD (C24.0) declined from 465 to 329. The decline in male cases was from 211 to 170, and in female cases from 254 to 159. In contrast, the US SEER data showed the rise in the total number of cases reported as IHBD (C22.1) rose much less during a
Discussion
This study includes the first European investigation to analyse the impact of possible misclassification of hilar/’Klatskin’ tumours on CC incidence rates using national cancer registration data for the whole of England and Wales together with an informative comparison of up-to-date data from a large cancer dataset in the US, and the first ever investigation of coding practice for CC by cancer registries, covering a large national population of almost 60 million people. ‘Klatskin’ and ‘hilar’
Conflict of interest
The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
Acknowledgements
We are grateful for support by the NIHR Biomedical Research Centre funding scheme at Imperial College London; the Alan Morement Memorial Fund (Essex, UK) and the Imperial College Healthcare Trustees (donations from Mr. and Mrs. Barry Winter). S.A.K. is also supported by the Higher Education Funding Council for England and the British Liver Trust. We thank the cancer registries in England and Wales and the Office for National Statistics for providing data on cancer registrations. We are grateful
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