Objectives: The distinction of clinically uncertain, poorly differentiated liver masses into primary liver cancer (PLC) of cholangiocytic origin (intrahepatic cholangiocarcinoma; CCA) or hepatocellular origin (hepatocellular carcinoma; HCC) vs. metastasis is highly relevant to guiding patient treatment. Protocols differ in terms of resection, local ablation, liver transplantation, or systemic therapies with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs). Methods: This retrospective case series exemplifies a multidisciplinary, practical guide to clinically uncertain liver masses using imaging, histomorphology, immune phenotyping, and mutational testing of telomerase promoter (TERT) combined with a literature review. Results: In 2/3 patients with uncertain liver masses and inconclusive immunohistochemistry profiles, TERT testing supported the diagnosis of poorly differentiated hepatocellular carcinoma. The third case with a history of sclerosing cholangitis and vague adenoid morphology yielded mutations in ARID1a and TP53 and was identified as primary liver cancer, consistent with poorly differentiated intrahepatic cholangiocarcinoma or mixed hepatocellular cholangiocarcinoma (cHCC/CCA). Conclusions: Finding HCC-typical TERT promoter mutations is a useful diagnostic tool in poorly differentiated primary liver cancer.