Correspondence
Lymphoma-Infiltrating Immune Cells
N Engl J Med 2005; 352:724-725February 17, 2005
- Article
To the Editor:
Dave et al. (Nov. 18 issue)1 report their findings concerning the molecular features of tumor-infiltrating immune cells in follicular lymphoma. This low-grade lymphoma includes heterogeneous subtypes that require different treatment strategies. Several important variables for predicting the prognosis of follicular lymphoma are lacking in this report. First, although the t(14;18)(q32;q21) mutation is the cytogenetic hallmark of follicular lymphoma, follicular lymphoma without this translocation exists and has distinct clinical features.2 Second, grades 1, 2, and 3a follicular lymphomas constitute a spectrum of indolent lymphoma, whereas grade 3b is similar to diffuse large lymphoma.3 Third, the presence of large, diffuse areas of lymphomatous cells in follicular lymphoma is associated with a poor prognosis. We would like to know the association between molecular features of tumor-infiltrating immune cells and these variables.
3 ReferencesKazuhiko Kobayashi, M.D., Ph.D.
Naoko Murashige, M.D.
Yukiko Kishi, Jr., M.D.
JR Tokyo General Hospital, Tokyo 151-8528, Japan1
Dave S ,Wright G ,Tan B , et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 2004;351:2159-2169
Full Text | Web of Science | Medline2
Horsman D ,Okamoto I ,Ludkovski O , et al. Follicular lymphoma lacking t(14;18)(q32;q21): identification of two disease subtypes. Br J Haematol 2003;120:424-433
CrossRef | Web of Science | Medline3
Ott G ,Katzenberger T ,Lohr A , et al. Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3. Blood 2002;99:3806-3812
CrossRef | Web of Science | Medline
To the Editor:
Dave et al. explore an important aspect of the biology of follicular lymphoma: the role of non-neoplastic cells. However, it is difficult to form hypotheses about molecular cross-talk between tumor cells and tumor-infiltrating immune cells on the basis of this study. In follicular lymphoma, the proportion and type of immune cells within the follicles differ from those outside the follicles, and these differences cannot be addressed without microdissection. Apart from selection according to CD14 and CD19 status, further positive selection to delineate different T-cell subgroups, follicular dendritic cells, and other cell types would have yielded crucial information.
The strategy of identifying gene-expression signatures has a shortcoming. It does not identify small sets of highly discriminatory molecules of prognostic or clinical significance. Thus, it does not help translation of the findings to simpler applications, such as immunohistochemistry. Identification of one or a few genes as the most informative within a signature, in terms of their being surrogate markers of the signature or master molecules regulating the expression of the rest of the genes, might be more beneficial for practical application.
Kikkeri N. Naresh, M.D.
Hammersmith Hospital, London W12 0HS, United Kingdom
k.naresh@imperial. ac. uk To the Editor:
Dave and colleagues performed gene-array analysis of whole-tumor biopsy specimens, which included both malignant cells and nonmalignant normal cells. The gene-expression signature from nontumor cells might be derived from tumor-infiltrating immune cells, as the authors claim, but it just as easily could be derived from surrounding tissue from the involved lymph node. The amount of normal surrounding lymph-node material could vary according to the size of the lymph node from which the biopsy specimen is obtained, the type of biopsy performed (excisional vs. core), or the aggressiveness with which the lymphoma cells are effacing the normal lymphoid architecture. If the last of these possibilities is indeed the case, then the gene-expression signatures reported by Dave and colleagues could represent an epiphenomenon in which aggressive lymphoma cells negatively affect surrounding immune cells, rather than a situation in which tumor-infiltrating immune cells control lymphoma growth. Immunohistochemical or in situ hybridization analysis for selected transcripts could be performed to determine whether the gene-expression signatures are present in immune cells infiltrating the tumor, as opposed to the surrounding normal lymph-node cells.
Thomas F. Gajewski, M.D., Ph.D.
University of Chicago, Chicago, IL 60637
tgajewsk@medicine.bsd. uchicago. edu Author/Editor Response
In response to Kobayashi et al.: our study deals primarily with the molecular mechanisms that underlie survival in follicular lymphoma. It is not clear from the literature that cytogenetic aberrations — including t(14;18)(q32;q21), tumor grade 3b, or the presence of areas containing diffuse large-B-cell lymphoma (except in grade 3 disease) — are consistently associated with survival in follicular lymphoma. The group of biopsy specimens that were grade 3b and the group that had diffuse areas each constituted less than 10 percent of the cases. Thus, it is not possible to draw conclusions regarding their associations with the immune-response gene-expression signatures with high statistical certainty.
In response to Dr. Naresh: there is a fundamental difference between immunohistochemistry and measurement of gene expression by microarrays; immunohistochemistry is a semiquantitative method, whereas gene-expression profiling is a highly quantitative method. Furthermore, immunohistochemistry can be easily performed for only a few proteins per biopsy sample. We found that we could not drop any genes from the survival signatures without losing some predictive power. This observation suggests that these genes provide a quantitative view of the complex biologic variation that underlies the clinical variability of follicular lymphoma. Thus, it would be quite difficult to design an immunohistochemistry assay that would accurately reflect our gene-expression–profiling results.
The study was not designed to delineate comprehensively the types of immune cells that affect long-term survival. Microdissection may be one way to study this area further. Multiparameter flow sorting for individual immune-cell populations, followed by DNA microarray analysis, would be another way to elucidate the cellular origin of the immune signatures in follicular lymphoma.
Dr. Gajewski suggests that the immune-response signatures may be surrogates for the aggressiveness of the lymphoma. This hypothesis suggests that biopsy specimens from the most aggressive lymphomas would show the greatest effacement of the lymph node and, consequently, the lowest expression of the immune-response signatures. Therefore, increased expression of the immune-response signatures would be expected to be associated with a good prognosis. The fact that one of the immune-response signatures was associated with a good prognosis and the other with a poor prognosis strongly suggests that the immune-response signatures are not simple surrogates for malignant effacement of the lymph node. Rather, they reflect complex differences in the nature of the infiltrating immune cells that are associated with the length of survival in follicular lymphoma.
Sandeep S. Dave, M.D.
Louis M. Staudt, M.D., Ph.D.
National Cancer Institute, Bethesda, MD 20892
lstaudt@mail.nih. gov
