Bile duct carcinoma C22.1

The so-called Bismuth classification dates back to the era of open cholecystectomy and was first described in 1982 (Hauser 2016).

Bile duct carcinoma is a heterogeneous group of epithelial neoplasms with predominantly cholangiocyte-type differentiation originating from the intrahepatic bile ducts proximal to the D. hepaticus dexter or sinister (Guidelines Program Oncology 2022).

CCA is divided into three different entities according to its anatomical site of origin (Kasper 2015):

- Intrahepatic CCA, so-called iCCA: Occurs in only about 10% (Preinfalk 2018). In iCCA, a distinction is made between "small duct", which phenotypically resembles small bile ducts, and "large duct", which resembles carcinomas of the extrahepatic bile ducts. Both types differ etiologically, histologically, molecularly, imaging and clinically, which is of increasing prognostic and therapeutic importance (Guidelines Program Oncology 2022).

- Perihilar CCA, so-called pCCA: Also referred to as central CCA. It is found in approximately 65% of all CCAs (Kasper 2015). It corresponds to the CCA of the hepatic bifurcation and is also called Klatskin tumor.

- Distal CCA, so-called dCCA: This is located below the cystic duct (Herold 2022) and is also called peripheral CCA. It is found in approximately 30% of CCAs (Kasper 2015).

These three entities differ in tumor biology, clinic, and therapy (Preinfalk 2018).

The most commonly used Bismuth classification to describe tumors and strictures of the biliary system and to classify acute bile duct lesions differentiates between (Hauser 2016):

- Type I: The tumor is located below the hepatic fork.

- Type II: The tumor involves the hepatic fork.

- Type III:

- Type III a: The tumor involves the right main branch of the hepaticus.

- Type III b: The tumor involves the left main branch of the hepaticus.

- Type IV: The tumor involves both main branches of the hepaticus (Herold 2022).

The TNM classification distinguishes between:

1. adenocarcinoma of intrahepatic bile ducts:

- TX: primary tumor not assessable

- T 0: No primary tumor detectable

- Tis: Carcinoma in situ

- T1: Solid tumor without vascular invasion detectable

- T 2 a: Solid tumor with vascular invasion detectable

- T2 b: Multiple tumors are found with and without vascular invasion

- T3: Tumors show perforation of visceral peritoneum or direct invasion of extrahepatic structures

- T4: Tumor is found with periductal invasion, the so-called periductal growth pattern (Possinger 2017)

- NX: Regional lymph nodes are not evaluable

- N0: No regional lymph node involvement

- N1: Evidence of regional lymph node metastases (Possinger 2017).

- M0: No evidence of distant metastases

- M1: Distant metastases present (Possinger 2017).

Stages according to UICC (Preinfalk 2018)

- Stage I: T1, N0, M0

- Stage II: T2, N0, M0

- Stage III: T3, N0, M0

- Stage IV A: T4, N0, M0 and any T, N1, M0

- Stage IV B: Any T, any N, M1 (Possinger 2017).

2nd adenocarcinoma of perihilar bile ducts:

- TX: Primary tumor not assessable.

- T 0: No primary tumor detectable

- Tis: Carcinoma in situ

- T1: Solid tumor confined to bile duct, extension into fibromuscular layer or muscularis propria

- T 2 a: The tumor already infiltrates the adjacent soft tissues of the bile duct

- T2 b: The tumor infiltrates the nearby liver parenchyma

- T3: Unilateral branches of the V. portae or the A. hepatica are already infiltrated by the tumor

- T4: The tumor infiltrates:

- the main branch of the V. portae or

- bilateral branches or

- A. hepatica communis or

- 2nd order bilateral branches or

- Unilateral branches of 2nd order bile duct with infiltration of contralateral branches of V. portae or A. hepatica (Possinger 2017).

- NX: Regional lymph nodes are not assessable

- N0: No regional lymph node involvement

- N1: Evidence of regional lymph node- metastases in the cystic duct, choledochal duct, along the portae vein and hepatic artery (Possinger 2017)

- M0: No evidence of distant metastases.

- M1: Distant metastases present (Possinger 2017).

- Stage 0: Tis, N0, M0

- Stage I: T1, N0, M0

- Stage II: T2a, T2 b, N0, M0

- Stage III A: T3, N0, M0

- Stage III B: T1, T2, T3, N0, N1, M0

- Stage IV A: T 4, any N, M0

- Stage IV B: Any T, any N, M1 (Possinger 2017).

3. adenocarcinoma of the distal extrahepatic bile duct.

- TX: primary tumor not assessable

- T 0: No primary tumor detectable

- Tis: Carcinoma in situ

- T1: Tumor is confined to the bile duct

- T 2 a: The tumor already infiltrates beyond the bile duct

- T3: Tumor infiltrates gallbladder, liver, pancreas, duodenum, and adjacent organs

- T4: The tumor infiltrates the mesenteric artery sup. or the truncus coeliacus (Possinger 2017)

- NX: Regional lymph nodes are not assessable

- N0: No regional lymph node involvement

- N1: Regional lymph node metastases are found (Possinger 2017).

- M0: No evidence of distant metastases

- M1: Distant metastases present (Possinger 2017).

- Stage 0: Tis, N0, M0

- Stage IA: T1, N0, M0

- Stage I B: T2, N0, M0

- Stage II A: T3, N0, M0

- Stage II B: T1, T2, T3, N1, M0

- Stage III: T 4, any N, M0

- Stage IV: Any T, any N, M1 (Possinger 2017).

CCA represents the second most common tumor of the liver next to hepatocellular carcinoma (HCC) (Preinfalk 2018).

The annual incidence of CCA is approximately 3: 100,000 and is increasing worldwide. In Southeast Asia, the incidence is highest with approximately 7,000 new cases annually, probably due to the high number of parasitic infections with liver fluke (Guidelines Program Oncology 2022).

The peak incidence of the disease is between 60 - 70 years (Herold 2022).

There are risk factors such as:

- chronic biliary tract inflammation (Herold 2022)

- primary sclerosing cholangitis (found in 10 - 20 % of patients [Kasper 2015])

- existing autoimmune disease

- alcoholic liver disease

- choledocholithiasis

- choledochal cysts (found in about 10 %)

- Liver flukes (in Asians), especially Opisthorchis viverrini and Clonorchis sinensis (Kasper 2015)

- liver cirrhosis

- chronic hepatitis C and hepatitis B infections (Guidelines Program Oncology 2022)

However, the vast majority of diseases occur without prior risk factors (Herold 2022).

In a 2013 study by Chaiteerakij et al, patients treated with metformin were found to have a significantly lower risk of developing CCA. However, there was no effect on survival time in the presence of CCA (Preinfalk 2018).

In CCA, early symptoms are usually absent. Typical is icterus without pain, so-called Courvoisier sign (Herold 2022).

iCCA sometimes leads to nonspecific symptoms such as abdominal pain and loss of appetite (Preinfalk 2018).

In dCCA and pCCA, persistent icterus with cholestasis is often found at a relatively early stage of disease (Preinfalk 2018).

In the advanced stage, pruritus usually occurs (Guidelines Program Oncology 2022).

- Physical examination:

On physical examination, an enlarged gallbladder may be palpable, and painless jaundice may also be present (Herold 2022).

Diagnosis is made by MRI and MRCP (Herold 2022) with biopsy (Kasper 2015).

Klatskin- tumor located at the bifurcation is often associated with a collapsed gallbladder. This requires imaging of the entire bile duct (Kasper 2015).

Abdominal sonography

Abdominal sonography is usually the first form of examination. Here, dilated bile ducts are seen in CCA (Kasper 2015). The tumor itself is usually iso- to hypoechogenic (Guidelines Program Oncology 2022).

If such changes are present, further clarification by MRI, MRCP (magnetic resonance cholangiopancreatography) or spiral CT is recommended (Kasper 2015).

Computed tomography

CT shows hypodense hepatic space involvement with irregular margins in the native phase, a hypervascular fringe in the arterial phase, and increasing enhancement in the venous phase (Guidelines Program Oncology 2022).

However, contrast-enhancing CT has limited ability to identify the location and spread along the bile ducts (Oncology 2022 guideline program).

MRI

Due to its superior soft tissue contrast to CT, MRI is considered the imaging modality of choice for both diagnosis and local staging (Oncology 2022 Guideline Program).

ERCP

Using invasive cholangiopancreaticography, it is possible:

- define the bile ducts

- to take a biopsy

- therapeutically decompress the blocked bile ducts by inserting stents (Kasper 2015).

Serological tumor markers are non-specific in CCA. CEA, CA 19- 9 and CA- 125 are frequently elevated (Kasper 2015).

For therapeutic reasons, fusions or rearrangements in the FGFR2 (fibroblast growth factors 2) gene play a role (Arnheim 2022).

In patients with iCCA, mutations in IDH 1 (isocitrate dehydrogenase 1) can be detected in up to 20% (Arnheim 2021).

Histologically, these are predominantly mucin-producing (Kasper 2015) adenocarcinomas. Only when occurring in childhood, an embryonal rhabdomyosarcoma is found (Herold 2022).

The tumor usually stains positive for cytokeratins 7, 8, and 19 and negative for cytokeratin 20 (Kasper 2015).

Histological differentiation from metastases from colon or pancreatic primary tumors is not possible (Kasper 2015).

- Carcinoma of the gastrointestinal tract metastasizing to the liver (it should be noted here that metastases are far more common in aggregate than CCAs (Guidelines Program Oncology 2022).

- Pancreatic head carcinoma (Herold 2022)

Therapy consists of surgical measures (see d.).

Palliative measures in hilar CCA may consist of:

- ERCP with stent insertion

- radiofrequency ablation (RFA)

- photodynamic therapy (Herold 2022):

Here, sodium porfimer is injected i. v. and photoactivated intraluminally with a red light laser (Kasper 2015).

- Bile drainage to the outside by PTCD.

- Chemotherapy with gemcitabine plus cisplatin or 5- FU (Herold 2022).

- Futibatinib

The tyrosine kinase inhibitor futibatinib results in a high response rate of up to 40% in patients with fusions or rearrangements in the FGFR2 (fibroblast growth factors 2) gene, according to recent studies by Arnheim (2022).

- Capecitabine

Preinfalk (2018) recommends adjuvant chemotherapy optionally after R0 resection. According to the BILCAP- study, capecitabine shows evidence of adjuvant therapy for the first time (Preinfalk 2018).

Surgical resection is the only curative treatment option, but due to the relatively late time of diagnosis, this is possible in only 10-20% of patients (Preinfalk 2018).

Surgical treatment is recommended exclusively in appropriately equipped centers (Herold 2022), as surgical therapy is very demanding due to the narrow anatomical conditions of the bile duct bifurcation, portal vein bifurcation, and hepatic arteries (Stavrou 2014).

If an R0 resection seems possible, a resection procedure in the form of an extended partial liver resection, the so-called trisectorectomy with en bloc resection of the extrahepatic bile ducts possibly also a partial portal vein resection and lymph node dissection should be performed in pCCA, dCCA and iCCA (Guidelines Program Oncology 2022).

However, in the course of surgical exploration, the option of R0 resection turns out to be feasible in only about 50% (Herold 2022).

In individual cases, liver transplantation (Herold 2022) with combined radiotherapy is performed (Kasper 2015). However, transplantation for iCCA should not be performed outside of trials because iCCA is a contraindication for liver transplantation due to early tumor recurrence and poor 5-year survival (Guidelines Program Oncology 2022).

Overall, the prognosis of CCA is poor. Median survival is between 2 - 6 months if inoperable. The 5-year survival rate is 5 - 10% and has not improved for 30 years (Preinfalk 2018).

Even after R0 resection, 5-year survival rates are only up to 30% (Herold 2022).

For combined radiotherapy with liver transplantation, the 5-year survival rate is up to 65% according to Kasper (2015).

1. Arnheim K (2022) Advanced bile duct carcinoma. Oncology World 13 (04) 245
2. Arnheim K (2021) Metastatic bile duct carcinoma: targeted therapies as a new hope. Oncology World 12 (02) 108 - 109.
3. Chaiteerakij R, Yang J D et al (2013) Risk factors for intrahepatic cholangiocarcinoma: association between metformin use and reduced cancer risk. Hepatology 57 (2) 648 - 655
4. Hauser H, Buhr H J, Mischinger H J (2016) Acute abdomen: diagnosis - differential diagnosis - primary care - therapy. Springer Verlag Vienna 193
5. Herold G et al (2022) Internal medicine. Herold Publishers 569 - 570
6. Kasper D L, Fauci A S, Hauser S L, Longo D L, Jameson J L, Loscalzo J et al (2015) Harrison's Principles of Internal Medicine. Mc Graw Hill Education 552 - 553
7. Oncology guideline program (German Cancer Society, German Cancer Aid, AWMF): Diagnosis and therapy of hepatocellular carcinoma and biliary carcinoma Long version 3.0, 2022, AWMF register number: 032/053OL https://www.leitlinienprogramm-onkologie.de/leitlinien/hcc-und-biliaere-karzinome/; accessed on [28/03/2023].
8. Possinger K, Regierer A, Eucker J (2017) Facharztwissen Onkologie. Elsevier Urban and Fischer Publishers Germany.
9. Preinfalk A (2018) Prognostic factors in patients with bile duct carcinoma - a retrospective analysis from a university center. Dissertation for the degree of Doctor of Medicine at the Medical Faculty of Ludwig-Maximilians-University in Munich, Germany.
10. Starvrou G A, Donati M, Faiss S, Jenner R M, Niehaus K J, Oldhafer K J (2014) Perihilar cholangiocarcinoma (Klatskin tumor). Surgeon 85 (2) 155 - 165