Product information and disease description Place of product in therapy Disease description

Diagnosis

11 evidence topics · 7 sources

Summary: diagnostic pathway and molecular profiling

Diagnosis rests on cross-sectional imaging followed by tissue confirmation, with the route to tissue determined by anatomic subtype. Contrast-enhanced CT and MRI are the reference imaging modalities; magnetic resonance cholangiopancreatography is used for perihilar and distal disease and endoscopic retrograde cholangiography provides biliary brushings for cytology and fluorescence in situ hybridization. Biliary cytology has low sensitivity for perihilar disease (43% in one meta-analysis) and FISH is more sensitive (65% versus 19% in one series). CA19-9 is the principal serum biomarker but lacks specificity. Histopathological or cytological confirmation is mandatory because no radiological pattern is specific for cholangiocarcinoma.

For the second-line setting, molecular profiling determines whether a targeted option exists. The Pan-Asian adapted ESMO guideline recommends a core biopsy for diagnostic pathology and molecular profiling before any non-surgical treatment and molecular analysis in advanced disease considered suitable for systemic treatment, and recommends ivosidenib for IDH1 mutations, FGFR inhibitors for FGFR2 fusions, pembrolizumab for MSI-H or dMMR tumours, and dabrafenib with trametinib for BRAF V600E tumours after at least one prior line. In a real-world series of 91 biliary tract tumours, comprehensive genomic profiling identified potentially actionable alterations in 21 participants (23.1%), yielded expert panel therapeutic options in 15 (16.5%), and led to genomically matched therapy in 7 (7.7%).

Diagnosis: guideline recommendations on pathology, molecular biology, and staging

“Molecular analysis is recommended in advanced disease considered suitable for systemic treatment [I, A]” (opens the source at this quote in a new tab)
“Elevated CA 19-9 is associated with poorer prognosis and can be useful for assessing response to treatment [III, C]” (opens the source at this quote in a new tab)
“Thoraco-abdomino-pelvic CT remains the reference examination for lymph node and metastatic extension [III, A]” (opens the source at this quote in a new tab)
“FDG-PET is not recommended for imaging of the primary tumour. However, it may be considered where there is clinical suspicion of nodal metastases, distant metastases and disease recurrence [III, C; consensus = 100%].” (opens the source at this quote in a new tab)
“Radiological imaging should be carried out before ERCP or PTC in patients with jaundice [III, A]” (opens the source at this quote in a new tab)

Diagnosis: guideline recommendations on tissue acquisition for molecular profiling

“A core biopsy should be obtained for diagnostic pathology and molecular profiling before any nonsurgical treatment [III, A].” (opens the source at this quote in a new tab)
“In patients with d/pCCA without extraductal metastasis, PTC- or ERCP-guided biopsies should be carried out to obtain adequate tissue for diagnostic pathology and molecular profiling [III, A].” (opens the source at this quote in a new tab)

Diagnosis: composition of the molecular testing panel

“Parallel sequencing of several genes using focused next-generation sequencing (NGS) is preferred over single gene testing.” (opens the source at this quote in a new tab)
“Currently, the gene panel should include the respective coding DNA regions (target regions) of isocitrate dehydrogenase 1 (IDH1), human epidermal growth factor receptor 2 (HER2)/neu [v-erb-b2 avian erythroblastic leukaemia viral oncogene homologue 2 (ERBB2)] and BRAF to test for hotspot mutations, but the rapidly evolving landscape of drug targets and predictive biomarkers may soon necessitate larger panels.” (opens the source at this quote in a new tab)

Diagnosis: guideline recommendations on second-line molecularly directed therapy

“Ivosidenib is recommended for the treatment of patients with CCA and IDH1 mutations who have progressed after ≥1 prior line of systemic therapy” (opens the source at this quote in a new tab)
“FGFR inhibitors are recommended for the treatment of patients with FGFR2 fusions who have progressed after ≥1 prior line of systemic therapy” (opens the source at this quote in a new tab)
“Pembrolizumab is recommended in patients with MSI-H/dMMR who have progressed on or are intolerant to prior non-immune checkpoint inhibitor-containing treatment” (opens the source at this quote in a new tab)
“Dabrafenib-trametinib is recommended for the treatment of patients with BRAFV600E mutations who have progressed after ≥1 prior line of systemic therapy” (opens the source at this quote in a new tab)

Diagnosis: imaging and tissue acquisition in intrahepatic cholangiocarcinoma

“iCCA is often seen at presentation as an intrahepatic mass and is incidentally found in 25–30% of patients” (opens the source at this quote in a new tab)
“Carbohydrate antigen 19-9 (CA19-9) is the primary serum biomarker used in CCA diagnosis, although it has subpar specificity and can be elevated in various conditions, such as biliary obstruction or pancreatic cancer.” (opens the source at this quote in a new tab)
“MRI may provide enhanced assessment of the primary mass, whereas CT imaging has superior detection of vascular enhancement and is, therefore, important in determining resectability” (opens the source at this quote in a new tab)
“Histopathological analysis of a biopsy specimen remains the mainstay for confirmation of an iCCA diagnosis.” (opens the source at this quote in a new tab)

Diagnosis: perihilar and distal cholangiocarcinoma

“Patients with pCCA and dCCA typically present with painless jaundice owing to underlying biliary obstruction.” (opens the source at this quote in a new tab)
“The sensitivity and specificity of MRCP to distinguish benign and malignant causes of hilar obstruction are 87% and 85%, respectively” (opens the source at this quote in a new tab)
“ERC has a diagnostic and therapeutic role in pCCA and dCCA as it enables detection of malignant strictures and acquisition of biliary brushings for cytology and fluorescence in situ hybridization (FISH) analysis.” (opens the source at this quote in a new tab)
“However, the sensitivity of biliary cytology for pCCA detection is low (43% according to one meta-analysis127). FISH analysis has a higher sensitivity than cytology (65% versus 19% in one series) and similar specificity for detection of CCA” (opens the source at this quote in a new tab)
“EUS–FNA has a higher sensitivity for detection of dCCA than detection of pCCA (81% versus 59%)” (opens the source at this quote in a new tab)

Diagnosis: histological confirmation and the limits of imaging

“As no specific CCA radiology pattern exists, histopathological or cytological analysis is mandatory to confirm the diagnosis1,28. This diagnosis is based on the WHO classification of biliary tract cancer showing an adenocarcinoma or mucinous carcinoma101, with tubular and/or papillary structures and a variable fibrous stroma102.” (opens the source at this quote in a new tab)
“CT is considered the standard imaging method for the preoperative assessment of both iCCA and pCCA; it provides a comprehensive evaluation of the primary tumour, the relationship with adjacent structures, and potential thoracic and abdominal spread” (opens the source at this quote in a new tab)

Diagnosis: staging and its limitations

“There is no widely used staging system for CCA, although it can be staged according to the American Joint Committee on Cancer (AJCC) TNM system103,104.” (opens the source at this quote in a new tab)
“Finally, the TNM classification misses relevant prognostic factors such as the presence of cancer-related symptoms (such as abdominal pain or malaise) or the degree of liver function impairment.” (opens the source at this quote in a new tab)

“Disease stage was defined as locally advanced versus metastatic as per the American Joint Committee on Cancer staging (version 7),21 according to which intrahepatic cholangiocarcinoma with multifocal or satellite liver lesions or metastases were classified as locally advanced in the absence of extrahepatic metastatic disease.” (opens the source at this quote in a new tab)

Diagnosis: yield of comprehensive genomic profiling in biliary tract tumours

“Reportable genomic alterations were detected in 88 patients (96.7%), whereas no reportable alteration was detected in three patients (3.3%).” (opens the source at this quote in a new tab)
“Potentially actionable genomic alterations were identified in 21 patients (23.1%). Expert panel-based therapeutic options were identified in 15 patients (16.5%), and genomically matched therapy was introduced in 7 patients (7.7%).” (opens the source at this quote in a new tab)
“Site-specific frequencies of potentially actionable alterations were highest in iCCA (17/46, 37.0%), followed by GBC (4/24, 16.7%), whereas no potentially actionable genomic alteration was identified in eCCA or ampullary tumors using this definition.” (opens the source at this quote in a new tab)

Diagnosis: misclassification as cancer of unknown primary

“The nonspecific clinical presentation, absence of distinguishable localizing symptoms, and lack of definitive pathologic diagnosis—combined with the typically late diagnosis of CCA—can lead to liver-dominant carcinomas being misclassified as cancers of unknown primary (CUP) origin.” (opens the source at this quote in a new tab)
“Therefore, patients with CUP often face protracted diagnostic journeys, rapidly spreading metastases, and median OS ranging from two to eight months.” (opens the source at this quote in a new tab)