PT  - JOURNAL ARTICLE
AU  - Albrecht, Thomas
AU  - Rossberg, Annik
AU  - Rose, Fabian
AU  - Breuhahn, Kai
AU  - Baumann, Eva-Marie
AU  - Tóth, Marcell
AU  - Brinkmann, Fritz
AU  - Charbel, Alphonse
AU  - Vogel, Monika Nadja
AU  - Köhler, Bruno
AU  - Mehrabi, Arianeb
AU  - Büchler, Markus Wolfgang
AU  - Singer, Stephan
AU  - Solass, Wiebke
AU  - Straub, Beate
AU  - Schirmacher, Peter
AU  - Roessler, Stephanie
AU  - Goeppert, Benjamin
TI  - Combined analysis of albumin in situ hybridisation and C reactive protein immunohistochemistry for the diagnosis of intrahepatic cholangiocarcinoma: towards a molecular classification paradigm
AID  - 10.1136/jcp-2024-209429
DP  - 2024 May 15
TA  - Journal of Clinical Pathology
PG  - jcp-2024-209429
4099  - http://jcp.bmj.com/content/early/2024/05/14/jcp-2024-209429.short
4100  - http://jcp.bmj.com/content/early/2024/05/14/jcp-2024-209429.full
AB  - Aims Intrahepatic cholangiocarcinoma (iCCA) is a diagnosis of exclusion that can pose a challenge to the pathologist despite thorough clinical workup. Although several immunohistochemical markers have been proposed for iCCA, none of them reached clinical practice. We here assessed the combined usage of two promising diagnostic approaches, albumin in situ hybridisation (Alb-ISH) and C reactive protein (CRP) immunohistochemistry, for distinguishing iCCA from other adenocarcinoma primaries.Methods We conducted Alb-ISH and CRP immunohistochemistry in a large European iCCA cohort (n=153) and compared the results with a spectrum of other glandular adenocarcinomas of different origin (n=885). In addition, we correlated expression patterns with clinicopathological information and mutation data.Results Alb-ISH was highly specific for iCCA (specificity 98.8%) with almost complete negativity in perihilar CCA and only rare positives among other adenocarcinomas (sensitivity 69.5%). CRP identified the vast majority of iCCA cases (sensitivity 84.1%) at a lower specificity of 86.4%. Strikingly, the combination of CRP and Alb-ISH boosted the diagnostic sensitivity to 88.0% while retaining a considerable specificity of 86.1%. Alb-ISH significantly correlated with CRP expression, specific tumour morphologies and small or large duct iCCA subtypes. Neither Alb-ISH nor CRP was associated with iCCA patient survival. 16 of 17 recurrent mutations in either IDH1, IDH2 and FGFR2 affected Alb-ISH positive cases, while the only KRAS mutation corresponded to an Alb-ISH negative case.Conclusions In conclusion, we propose a sequential diagnostic approach for iCCA, integrating CRP immunohistochemistry and Alb-ISH. This may improve the accuracy of CCA classification and pave the way towards a molecular-guided CCA classification.Data are available upon reasonable request. The datasets generated during and/or analysed during the current study are not publicly available, but are available from the corresponding author on reasonable request.