The 11th revision of the International Statistical Classification of Disease and Related Health Problems and Cholangiocarcinoma

The World Health Organisation (WHO) classifies clinical diagnoses with the International Statistical Classification of Disease and Related Health Problems (ICD). There have been various iterations of ICD since it is inception. For oncology, ICD-O was introduced in 1976 as a special adaption of ICD for cancers to facilitate greater coding detail of the topography, which describes the anatomical location of the tumour origin, and the morphology concerns the histology of a neoplasm. ICD-10 began in 1983 and was first used in 1994. At the same time, a code for cholangiocarcinoma (CCA) was also introduced (https://icd.who.int/browse10/2010/en).

CCA accounts for approximately 15% of primary liver cancers and ranks as the second most commonly diagnosed primary liver malignancy (1). Categorization by the site of the biliary anatomical tree, CCA is generally divided into intrahepatic and extrahepatic CCA (iCCA and eCCA). The former is located within the second-order bile ducts and the latter is distal to iCCA. For eCCA, it is subdivided into perihilar CCA (pCCA), the mass lesions are located in the left, right or common hepatic ducts, and distal CCA (dCCA), tumours arise from the common bile duct. Amongst CCA, pCCA is the most common subtype of CCA, accounting for 50–60% of the cases with 20–30% of dCCA and 10–20% of iCCA (1,2).

Over the past few decades, the incidence of CCA has increased globally. While the incidence of eCCA is relatively stable or decreased, iCCA is consistently increasing (3). The incidence of pCCA remains unclear as these could have been classified as iCCA or pCCA depending on the ICD system in place.

ICD-10 codes iCCA with C22.1 and eCCA with C24.0, but has no specific code for pCCA. ICD-O does have a separate histology code for pCCA with 8162/3, but unfortunately this is sometimes incorrectly cross-referenced to iCCA or eCCA. A recent retrospective analysis of 625 CCA cases across 3 independent UK regional hepatobiliary centres adopting ICD-10 found that of 226 iCCA cases reported, only 43% were coded correctly, while 34% were actually pCCA. Moreover, 92% of all pCCA cases were incorrectly coded as iCCA (4). Such incorrect coding could lead to inaccurate epidemiological data and published trends of CCA.

On 1st January 2022, ICD-11 was introduced (https://icd.who.int/en/docs/icd11factsheet_en.pdf) as the different topography and morphology of tumours are taken into account for the coding. The new code 2C12.10 is for iCCA, 2C18.0 for malignant neoplasms of perihilar bile duct, and 2C15.0 for dCCA, such as adenocarcinoma of biliary tract distal bile duct (Figure 1). This heterogeneous malignant group exerts the unique profiles of epidemiology, risk factors, pathophysiology, clinical manifestations and management.

Figure 1 The subtypes of CCA with three individual codes in ICD-11. Based on the different topography and morphology of CCA, ICD-11 codes 2C12.10 for intrahepetic cholangiocarcinoma, 2C18 for malignant neoplasms of perihilar bile duct, and 2C15.0 for adenocarcinoma of biliary tract distal bile duct. CCA, cholangiocarcinoma.

There are different risk factors for the subtypes of CCA. Although most cases of CCA arise sporadically, known risk factors for CCA generally include obesity and non-alcoholic fatty liver disease and more commonly include infection with liver flukes or hepatitis B and C, choledochal cyst, choledocholithiasis and chronic pancreatitis, depending on geodemographic regions (1).

At early stages, the development of CCA is often asymptomatic; some patients might experience vague symptoms, with the right-upper quadrant abdominal pain, weight loss, fever or fatigue. At late stages, however, clinical features of iCCA generally present with a constant, dull abdominal pain, while pCCA and dCCA can be the painless but present with jaundice, pale faeces and dark urine, and itchy skin (5).

Surgery is the only potential curative treatment of CCA if it is diagnosed early and has not disseminated (1). This will involve resecting all or parts of the bile duct, as well as parts of other organs or the surrounding lymph nodes. When diagnosed late, the metastasis occurs, the malignant mass is inoperable and refractory. For patients with pCCA, the surgical treatment will help control some symptoms to unblock the bile duct or stop it getting blocked or bypass a blockage. For iCCA, a subset of patients may be considered for resection of a liver (6), but recurrence after curative surgery is common (7).

Even though there are distinct anatomical entities of CCA with particular prognoses after surgical resection, the oncological treatment remains the same for most of them. The adjuvant capecitabine chemotherapy has been adopted by the wider community as the ideal choice for treatment as per the BILCAP study (8). The study failed to meet its primary endpoint by intention-to-treat analysis, though the preplanned sensitivity analysis highlighted a survival benefit (8). This space is suspected to change with the results of the ATTICA study in the next year or so. If the disease is deemed unresectable (i.e., locally advanced) or has spread to become metastatic, the treatment is broadly the same. First line treatment is with gemcitabine and cisplatin. In ABC-02, it was established that the doublet regime of gemcitabine and cisplatin improved overall survival to 11.7 months against 8.1 months for gemcitabine (9). According to the recent presentation of the TOPAZ-1 study in ASCO-GI 2022, gemcitabine and cisplatin combined durvalumab immunotherapy (targeting PD-L1) improved overall survival, progression free survival and overall response rate, although the data have not been formally published as a manuscript so far (https://clinicaltrials.gov/ct2/show/NCT03875235). Second line treatment has been established in the ABC-06 trial by comparing the regime FOLFOX with best supportive care with survival at 6 months being 50% against 35% (10). Furthermore, there are significant clinical trials with positive results by targeting oncogenic mutant molecules in CCA. BRAF V600E mutations are present in 5% of biliary cancers. The ROAR phase 2 study with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) showed a response rate of 50% with a progression free survival of 9.1 months. This is a significant advancement for this subset of patients (11). Fibroblast growth factor receptor 2 (FGFR2) alterations are present in approximately 15% of iCCA. Two significant trials have been conducted in this enriched population with pemigatinib and infigratinib. Pemigatinib had a slightly better progression free survival with 62% at 6 months (12,13). Isocitrate dehydrogenase 1 (IDH1) mutations are found in approximately 13% of iCCA and 1% in the rest. The ClarIDHy phase 3 trial tested the IDH1 inhibitor ivosidenib with CCA with this mutation in the treatment refractory setting (14). Six-month progression-free survival was 32% in the ivosidenib group in comparison with 0% in the placebo group (14).

Overall, ICD-11 allows us for better understanding of CCA to avoid skewing rates of morbidity and mortality, to identify a patient suitability for clinical trials, and to select different operating procedures associated with expertise, theatre time, equipment, hospital length stay.

The purpose of the present article intends to publicise the new code for CCA. The Global Cholangiocarcinoma Alliance (GCA) has designed the educational materials to support the adoption of ICD-11 among healthcare professionals and those involved in coding (https://globalccaalliance.com/en/resources).

Acknowledgments

The background of this work was based on CODING AHEAD website (https://www.codingahead.com/malignant-neoplasms-of-intestine-definitions-icd-11-codes) and presented as a Webinar in the Global Cholangiocarcinoma Alliance website (https://globalccaalliance.com/en/the-alliance). We would like to acknowledge the speakers who presented at the Webinar—Professor Shahid Khan, Mr. Hassan Malik, Dr. Robert Jakob, and Professor John Bridgewater and thank Professor Shahid Khan and Mr. Hassan Malik for reviewing this article.

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Hepatobiliary Surgery and Nutrition. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-22-69/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol 2020;17:557-88. [Crossref] [PubMed]
2. Rizvi S, Gores GJ. Emerging molecular therapeutic targets for cholangiocarcinoma. J Hepatol 2017;67:632-44. [Crossref] [PubMed]
3. Bertuccio P, Malvezzi M, Carioli G, et al. Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma. J Hepatol 2019;71:104-14. [Crossref] [PubMed]
4. Selvadurai S, Mann K, Mithra S, et al. Cholangiocarcinoma miscoding in hepatobiliary centres. Eur J Surg Oncol 2021;47:635-9. [Crossref] [PubMed]
5. Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut 2002;51:VI1-9. [Crossref] [PubMed]
6. Si A, Li J, Xing X, et al. Effectiveness of repeat hepatic resection for patients with recurrent intrahepatic cholangiocarcinoma: Factors associated with long-term outcomes. Surgery 2017;161:897-908. [Crossref] [PubMed]
7. Farges O, Fuks D, Boleslawski E, et al. Influence of surgical margins on outcome in patients with intrahepatic cholangiocarcinoma: a multicenter study by the AFC-IHCC-2009 study group. Ann Surg 2011;254:824-29; discussion 830. [Crossref] [PubMed]
8. Primrose JN, Fox RP, Palmer DH, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol 2019;20:663-73. [Crossref] [PubMed]
9. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010;362:1273-81. [Crossref] [PubMed]
10. Lamarca A, Palmer DH, Wasan HS, et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol 2021;22:690-701. [Crossref] [PubMed]
11. Subbiah V, Lassen U, Élez E, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol 2020;21:1234-43. [Crossref] [PubMed]
12. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol 2020;21:671-84. [Crossref] [PubMed]
13. Javle M, Lowery M, Shroff RT, et al. Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma. J Clin Oncol 2018;36:276-82. [Crossref] [PubMed]
14. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2020;21:796-807. [Crossref] [PubMed]