Diagnostic Approach for CK7-Negative/CK20-Negative Liver Biopsy

Primary Diagnostic Considerations

The French Association for the Study of the Liver recommends that a CK7-negative/CK20-negative adenocarcinoma on liver biopsy requires immediate expanded immunohistochemical workup to identify the primary site, as this atypical phenotype has poor predictive value and represents an unexpected pattern that cannot reliably guide clinical investigation without additional markers 1, 2
Hepatocellular carcinoma (HCC) is the most critical diagnosis to exclude, particularly in patients with chronic liver disease or cirrhosis, and requires hepatocellular markers (HepPar-1, glypican-3, Arginase-1, alpha-fetoprotein) and/or canalicular markers (CEA, CD10, BSEP) for confirmation, according to the French Association for the Study of the Liver guidelines 1, 2, 3, 4
Metastatic colorectal carcinoma can present with a CK7-/CK20- pattern, although this is an unusual profile, occurring in approximately 5% of colorectal metastases, as noted by the French Association for the Study of the Liver 1, 5, 6
Prostate adenocarcinoma (in males) must be excluded using PSMA and/or NKX3.1 markers, as recommended by the European Society for Medical Oncology 7, 8
Breast carcinoma (in females) requires GATA3 and/or SOX10 staining for evaluation, according to the European Society for Medical Oncology 7, 8

The French Association for the Study of the Liver guidelines recommend an immediate next-step approach based on a first-line panel (priority markers) including CDX2 or SATB2, TTF1, GATA3 (in women), CRP (C-reactive protein), and HepPar-1, glypican-3, Arginase-1 to exclude hepatocellular carcinoma 2, 4, 5, 6
A second-line panel (based on clinical context) may include PSMA and/or NKX3.1 (in men), synaptophysin and/or INSM1, SOX10 and/or S100, and renal markers, as recommended by the European Society for Medical Oncology 7, 8

Multiphase CT of chest, abdomen, and pelvis is required to search for extrahepatic primary sites, according to the French Association for the Study of the Liver guidelines 2, 4, 5, 6
Upper gastrointestinal endoscopy should be discussed in a multidisciplinary tumor board to eliminate gastric cancer, as recommended by the French Association for the Study of the Liver 1, 3
FDG-PET scan may be considered if doubt persists regarding liver metastases versus primary tumor, to identify occult extrahepatic primary, according to the French Association for the Study of the Liver guidelines 2, 4, 5, 6