Disturbed expression of the T-cell receptor/CD3 complex and associated signaling molecules in CD30+ T-cell lymphoproliferations

Abstract

Background: CD30(+) T-cell lymphoproliferations comprise a spectrum of clinically heterogeneous entities, including systemic anaplastic large cell lymphomas (ALK(-) and ALK(+)) and primary cutaneous CD30(+) T-cell lymphoproliferative disorders. While all these entities are characterized by proliferation of highly atypical, anaplastic CD30(+) T cells, the expression of T-cell specific antigens in the tumor cells is not consistently detectable.

Design and methods: We evaluated biopsies from 19 patients with primary cutaneous CD30(+) lymphoproliferative disorders, 38 with ALK(-) and 33 with ALK(+) systemic anaplastic large cell lymphoma. The biopsies were examined for the expression of T-cell receptorαβ/CD3 complex (CD3γ, δ, ε, ζ), transcription factors regulating T-cell receptor expression (ATF1, ATF2, TCF-1, TCF-1α/LEF-1, Ets1), and molecules of T-cell receptor-associated signaling cascades (Lck, ZAP-70, LAT, bcl-10, Carma1, NFATc1, c-Jun, c-Fos, Syk) using immunohistochemistry.

Results: In comparison to the pattern in 20 peripheral T-cell lymphomas, not otherwise specified, we detected a highly disturbed expression of the T-cell receptor/CD3 complex, TCF-1, TCF-1α/LEF-1, Lck, ZAP-70, LAT, NFATc1, c-Jun, c-Fos and Syk in most of the systemic anaplastic large cell lymphomas. In addition, primary cutaneous CD30(+) lymphoproliferative disorders showed such a similar expression pattern to that of systemic anaplastic large cell lymphomas, that none of the markers we investigated can reliably distinguish between these CD30(+) T-cell lymphoproliferations.

Conclusions: Severely altered expression of the T-cell receptor/CD3 complex, T-cell receptor-associated transcription factors and signal transduction molecules is a common characteristic of systemic and cutaneous CD30(+) lymphoproliferations, although the clinical behavior of these entities is very different. Since peripheral T-cell lymphomas, not otherwise specified retain the full expression program required for functioning T-cell receptor signaling, the differential expression of a subset of these markers might be of diagnostic utility in distinguishing peripheral T-cell lymphomas, not otherwise specified from the entire group of CD30(+) lymphoproliferations.

Figure 1.

Schematic overview of the TCR/CD3-associated signaling cascades. Molecules investigated immunohistochemically are highlighted in dark gray boxes.

Figure 2.

Bar chart of the TCR/CD3 complex expression data. For each entity, the percentage of cases that express a certain number of subunits (TCRβ, CD3δ, ɛ, γ, ζ) is plotted. Only cases for which expression data for all five TCR/CD3 subunits could be obtained are included [9 cases of lymphomatoid papulosis (LYP), 10 of cutaneous ALCL (cALCL), 36 ALK- systemic ALCL (sALCL), 33 ALK⁺ systemic ALCL (sALCL), 15 PTCL-NOS].

Figure 3.

Immunostaining of TCR/CD3 complex subunits and transcription factors regulating TCR expression. The left column shows characteristic staining results for lymphomatoid papulosis, the middle column shows results for an ALK⁻ systemic ALCL and the right column shows results for an ALK⁺ systemic ALCL. Scoring results are provided below the respective molecule (from left to right).

Figure 4.

Immunostaining of TCR/CD3 complex-associated signal transduction molecules. The left column shows characteristic staining results for lymphomatoid papulosis, the middle column shows results for an ALK⁻ systemic ALCL, and the right column shows results for an ALK⁺ systemic ALCL. Scoring results are provided below the respective molecule (from left to right).