Primary Nasal NK/T Cell Lymphoma: Cytology and Level of the Antiapoptotic PI9 Protein Have Prognostic Relevance.

Nasal NK/T cell lymphoma is a rare disease entity characterized by a nasopharyngeal presentation, a common origin from NK cells, an association with EBV and a predilection for Asians and South Americans contrasting with its rarity in Western countries. Several studies (Chim C.S. et al., Blood 2004; Li C.C. et al., Cancer 2004) indicate that the disease has a poor outcome following conventional combined chemoradiotherapy treatments, which might be related to resistance to therapy-induced apoptosis. It has been shown (Hermine O. et al., Blood 1996; Ten Berge R. et al., Blood 2002) that high level of expression of antiapoptotic proteins by lymphoma cells is associated with poor outcome in a variety of lymphomas.

In a retrospective analysis of 37 patients treated with first-line chemotherapy (n=34) or chemoradiotherapy (n=3) according to the LNH87, LNH93 and LNH98 trials of the GELA, we have analyzed by immunohistochemistry the expression of the granzyme B-protease inhibitor 9 (PI9) regarded as an inhibitor of apoptosis, and of the active form of caspase-3 (aC-3), an effector of apoptosis. The diagnosis was based on biopsies of the upper respiratory tract showing a proliferation of neoplastic cells with a CD3+/CD5− (100%), CD56+ (90%), TIA1/GrB+ (100%) phenotype and EBV association (100%). Among the 37 patients, 73% were < 60y, 68% were male. 76% had stage I, 5% Stage II, 19% stage IV and 68% had an IPI score of 0–1. With a median follow-up of 6.3 y, 5y-event-free and overall survivals were 38% and 47%, respectively. According to cytology, tumors were subclassified into predominatly small cell (52%) and predominatly large cell (48%) categories. PI9 was scored as positive (>10% of tumor cells) in 68% of the cases, whereas 35% were assigned a high number (>10 per field at high magnification) of aC-3 positive tumor cells. Univariate analysis showed that small cell cytology and absence of PI9 expression were associated with poor outcome, but not the level of aC-3 expression nor IPI score. By multivariate analysis, cytology and PI9 downregulation were shown to independently affect event-free (P=0.01 and 0.05, respectively) and overall survival (P=0.009 and 0.006). We conclude that nasal NK/T cell lymphomas disclose cytological heterogeneity which has prognostic relevance. We also found that lack of expression of PI9 is associated with poor outcome, an unexpected finding in view of the known antiapoptotic function of this protein. Since PI9 is constitutively expressed by normal NK cells, it might be postulated that its impaired expression in tumor cells reflects a yet unknown mechanism associated with progression.