The diagnosis of cHL is based on the identification of the characteristic Hodgkin and Reed-Sternberg (HRS) which represent 1–3% of all cell and are immersed in a background of small lymphocytes, histiocytes, epithelioid histiocytes, neutrophils, eosinophils, plasma cells, fibroblasts and vessels. The neoplastic cell population include (a) the Reed-Sternberg cells with large cytoplasm, two to multiple nuclei and acidophilic or amphophilic nucleoli and the Hodgkin cells with a large single nuclei and prominent eosinophilic nucleoli. The development of HRS is obscure. It has been postulated that these cells arise from mononucleated Hodgkin cells via endomitosis; however, recently Rengstl et al. [9] by tracking the cells and their progeny for multiple generations demonstrated that the fusion of daughter cells, called re-fusion, plays an essential role in the formation of HRS cells.

Based on the characteristics of the reactive infiltrate and the morphology of HRS cells, four histological subtypes are described: nodular sclerosis, mixed cellularity, lymphocyte rich and lymphocyte depleted.

The immunophenotype of cHL cells is characterized by the expression of CD30 (in more than 98% of cases) and CD15 (in about 75–80% of cHLs) and lack of CD45. Despite their B-cell genotype, cHL cells are negative for B-cell molecules (i.e. CD19, CD20, CD22), but PAX-5 is generally weaker than in normal B-cells. EBV infection is found in a variable percentage of cHL patients, and it is reported in approx. 20–40% of nodular sclerosis and lymphocyte depleted and 50–75% of mixed cellularity.