PurposeDuctal carcinomas (DCs) of the lacrimal gland are very rare but aggressive malignancies. We investigated DC of the lacrimal gland for potentially clinically actionable targets in the search for new therapeutic options. MethodsCase 1: A 77-year-old man, presented with diplopia and xerophtalmia; case 2: A 53-year-old man, presented with headache, proptosis and chemosis and case 3: A 73-year-old man, presenting with chemosis and a corneal abscess. All three cases were characterized morphologically including immunohistochemistry and genetically with fluorescence insitu hybridization (FISH) and one case with next-generation sequencing (NGS) of cancer relevant genes. ResultsCases 1 and 3 were composed of large, rounded, irregular cystic nodules of carcinoma cells with prominent central comedonecrosis, whereas case 2 had a scirrhous morphology. High expression of CK7, CK19, EMA, p53 and HER2 was characteristic for all three tumours. Androgen receptor was intensely positive in case 1, in scattered cells in case 2 and negative in case 3, whereas oestrogen and progesterone receptor were consistently negative. Genetically, a hemizygous deletion and a point mutation in PTEN were identified in case 1, whereas HER2 amplification was found in cases 2 and 3. ConclusionThis study identified a spectrum of genetic events and pattern of protein expression in DC of the lacrimal gland similar to a subset of carcinomas of the breast and ductal carcinomas of the salivary glands. For therapeutic purposes, aberrations in several components of especially the HER2 signalling pathway could alleviate the effect of HER2-directed therapy illustrating an inadequacy of isolated HER2 testing.