Elsevier

Journal of Hepatology

Volume 56, Issue 4, April 2012, Pages 848-854
Journal of Hepatology

Research Article
Rising trends in cholangiocarcinoma: Is the ICD classification system misleading us?

https://doi.org/10.1016/j.jhep.2011.11.015Get rights and content

Background & Aims

Cholangiocarcinomas (CC) can be sub-divided into intrahepatic (IHCC) or extrahepatic (EHCC). Hilar or ‘Klatskin’ tumours are anatomically extrahepatic. Most international studies, also from the UK, report increasing IHCC and decreasing EHCC incidence. The second edition of the International Classification of Diseases for Oncology (ICD-O-2) assigned ‘Klatskin’ tumours a unique histology code (8162/3), but this was cross-referenced to the topography code for intrahepatic (IHBD) rather than extrahepatic bile duct tumours (EHBD). Under the third ICD-O edition, ‘Klatskin’ tumours are cross-referenced to either IHBD or EHBD. New editions of the ICD-O classification are adopted at different time points by different countries. We investigated the impact of changing ICD-O classifications and the potential misclassification of hilar/’Klatskin’ tumours on bile duct tumour and CC incidence rates in England and Wales and the US. We also examined whether coding practices by cancer registries in England and Wales could be influencing these rates.

Methods

We analysed age-standardised incidence rates (ASIR) in England and Wales for IHBD and EHBD tumours between 1990 and 2008, then transferred all ‘Klatskin’ tumours from IHBD to EHBD and reanalysed rates from 1995, when ICD-O-2 was introduced in the UK. We also compared trends in IHBD, EHBD, and ‘Klatskin’ tumours in England and Wales with those in the USSEER (Surveillance, Epidemiology and End Results) database. Coding practice at Cancer registry level in England and Wales was investigated via a questionnaire completed by all national cancer registries.

Results

In England and Wales, 1990–2008, ASIR of IHBD cancers rose (0.43–1.84/100,000 population in males; 0.27–1.51 in females) but fell for EHBD (0.78–0.51/100,000 population in males; 0.62–0.39 in females). After transferring all ‘Klatskin’ tumours from IHBD to EHBD, there remained a marked increase in ASIR of IHBD cancers and a decrease in ASIR for EHBD, as only 1% of CC were reportedly ‘Klatskin’. The US SEER data showed that ASIR for IHBD gradually rose from 0.59/100,000 population in 1990 to 0.91 in 2001, then sharply fell before plateauing at 0.60 by 2007. ASIR for EHBD remained relatively stable at around 0.80/100,000 population until 2001, then began increasing, to 0.97 by 2007. Annually, between 1995 and 2008, the vast majority of ‘Klatskin’ tumours in England and Wales were coded as IHBD. This was also the case in the SEER data until 2001, when the situation was reversed and subsequently most ‘Klatskin’ tumours were coded as EHBD. US trends coincide with a switch from ICD-O2 to ICD-O-3 in 2001. In the UK, the switch to ICD-O-3 only occurred in 2008. On questioning, cancer registries in England and Wales stated they would not code a CC described as ‘hilar’ with the designated ‘Klatskin’ histology code. If the tumour site is unspecified, most registries classify CC as intrahepatic.

Conclusions

Changes in ICD-classification may be influencing observed changes in IHBD and EHBD incidence rates. Coding misclassification is likely to have been skewing CC registration to an intrahepatic site, thereby contributing to the previously reported rise in intrahepatic tumours.

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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