Primary adrenal diffuse large B-cell lymphoma (PA-DLBCL) is a rare subtype of extranodal DLBCL. Because of the rarity of this disease, its morphologic and genetic features are not comprehensively studied. Here, we systematically reviewed the clinicopathologic features of 42 cases of PA-DLBCL from our institution and investigated the frequency of MYD88 L265P and CD79B (exon 5) mutation in 29 eligible cases using Sanger sequencing. Clinically, PA-DLBCL was predominant in elderly male patients with advanced clinical stage and poor outcomes. Morphologically, the tumors often showed a sinusoidal and/or cohesive pattern with condensed chromatin and inconspicuous nucleolus which mimicked neuroendocrine carcinoma. Moreover, increased Reed-Sternberg-like cells were observed frequently. These confounding morphologic manifestations may lead to misdiagnosis. Genetically, PA-DLBCL harbored a high prevalence of MYD88 L265P (24%) and CD79B mutations (52%) which may be involved in lymphomagenesis. The CD79B mutation was significantly associated with a worse prognosis. A novel Histo-Molecular Classification system (4 categories) was proposed based on correlation with genetic changes. Generally, the neuroendocrine carcinoma-like type was associated with CD79B mutation, whereas the RS-like cell type indicated MYD88 L265P. The biphasic type was correlated with coexisting mutations of MYD88 and CD79B, whereas the common type implied no mutation. Furthermore, the common type showed significantly better survival. In conclusion, the proposed new category system could indicate the genetic changes as well as facilitate risk stratification to guide treatment and predict prognosis. Although this study augmented our understanding of PA-DLBCL, further analysis is required to validate our results and extend them to extranodal DLBCL at other sites.