NPM-ALK chimeric transcripts, encoded by the t(2;5), lead to an aberrant expression of ALK by CD30+ systemic lymphomas. To determine if t(2;5) is involved in cutaneous lymphoproliferative disorders, we studied 37 CD30+ cutaneous lymphoproliferations, 27 mycosis fungoides (MF), and 16 benign inflammatory disorders (BID). NPM-ALK transcripts were detected by nested reverse transcription-polymerase chain reaction (RT-PCR) in 1 of 11 lymphomatoid papulosis (LyP), 7 of 15 CD30+ primary cutaneous T-cell lymphoma (CTCL), 3 of 11 CD30+ secondary cutaneous lymphoma, 6 of 27 MF, and 1 of 16 BID. However, the expression of NPM-ALK transcripts was not associated with ALK1 immunoreactivity in MF, LyP, or BID cases. Only 1 CD30+ primary CTCL and 3 CD30+ secondary cutaneous lymphoma were ALK1 immunoreactive. The ALK1+ cases were also characterized by amplification of tumor-specific genomic breakpoints on derivative chromosome 5. These cases, except for 1 secondary cutaneous lymphoma, were also characterized by reciprocal breakpoints on derivative chromosome 2, leading to the expression of reciprocal ALK-NPM transcripts. Amplification of chromosomal breakpoints on both derivative chromosomes could represent an alternative to conventional cytogenetics for the diagnosis of t(2;5) and seems to be more reliable than the detection of cryptic NPM-ALK transcripts by nested RT-PCR.