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B-cell content in advanced-stage cHL
Table 2. Correlation analyses of whole-slide image analysis-determined CD3, CD20, CD30 and CD68 content in the study cohort.
CD68-positive area rate CD20-positive cell rate CD3-positive cell rate CD30-positive area rate Rho/P Rho/P Rho/P Rho/P
CD68-positive area rate
CD20-positive cell
rate
CD3-positive cell rate
CD30-positive area
rate
1
-0.05289
0.3389
0.15472 0.0049
0.21218
0.0001
-0.05289 0.3389
1
0.42374 / <0.0001
-0.07154 / 0.1956
0.15472 0.0049
0.42374 / <0.0001
1
0.15024 / 0.0063
0.21218 0.0001
-0.07154 / 0.1956
0.15024 / 0.0063
1
Rho: Pearson correlation coefficients; P= probability > |r| under the null hypothesis: Rho=0.
Table 3. Whole-slide image analysis-determined CD20-positive cell rates at baseline according to progression-free survival-failure status. CD20-positive cell rates (%)
All patients
CD20-negative
CD20-positive
Mixed cellularity
Nodular sclerosis
Lymphocyte-depleted
Lymphocyte rich
PFS: progression-free survival.
PFS failure
no yes
no
yes
no yes
no
yes
no yes
no
yes no
yes
N (%)
229 (67.4) 111 (32.6)
184 (67.4)
89 (32.6)
45 (67.2) 22 (32.8)
70 (70.0)
30 (30.0)
145 (65.6) 76 (34.4)
3 (0.75)
1 (0.25) 6 (0.67)
3 (0.33)
Group mean
17.7 13.5
18.1
12.4
16.3 17.9
19.5
13.3
16.9 12.1
2.4
5.5 32.2
55.7
P-value 0.0079
0.0002
n.s.
0.0064
0.0033
n.s.
n.s.
PFS failure
no yes
no
yes
no yes
no
yes
no yes
no
yes no
yes
N (%)
201 (69.4) 45 (30.6)
not available
not available
20 (80)
5 (20)
145 (65.6) 76 (34.4)
0
0
4 (100)
0
Group mean
21.5 16.4
20.8
14.4
16.9 12.1
0
0 18.2
P-value 0.0616
0.2529
0.0274
not
applicable not
applicable
Study cohort
Validation cohort
higher levels of event-free survival than the levels achieved with ABVD-based regimens.21 However, the prognostic relevance of macrophage content was absent despite the fact that we enriched the cohort for patients who had events signifying progression. It is important to mention that we excluded all non-cHL and all non-treat- ment-related deaths (n=55 in the study cohort) from all the analyses in order to identify a biomarker of lymphoma aggressiveness that was not biased by unrelated deaths. However, inclusion of those 55 patients as progression- free survival failures did not affect the overall results obtained within this study (data not shown).
One might speculate that the BEACOPP regimen reduced lymphoma-related events and that biomarkers established in patients treated with ABVD might lose their prognostic power. Recently published results on the prog- nostic range of the IPS in patients with advanced-stage cHL enrolled on the Eastern Cooperative Oncology Group 2496 trial do in fact argue for such an interpretation.27 In the aforementioned study, two factors (age and stage) were significantly associated with freedom from progres- sion in a multivariate analysis.27 Similarly, we found that apart from low B-cell content, only male sex and age were predictive of treatment failure in a multivariate analysis. Similar findings were reported by the Spanish Hodgkin Lymphoma Study Group in an analysis of patients with advanced-stage cHL treated with ABVD.28 We thus believe that our study cohort is representative of the population of
advanced-stage cHL patients and the absence of a prog- nostic significance of macrophage content is most likely due to the effective treatment applied.
In light of the fact that the BEACOPP-treated popula- tions analyzed in our study had very few lymphoma-relat- ed events (progression or relapse), the value of CD20 con- tent by WSI as a prognostic tool appears to be even higher. B-cell content in the microenvironment of cHL has been identified in several previous studies as a prognostic tool if analyzed by gene expression profiling or immunohisto- chemistry.12,16,17,29,30 However, this biomarker has so far attracted less attention compared to the macrophage count. Gene expression profiling of the cHL microenviron- ment is a laborious technology that is not widely avail- able. In addition, gene expression analysis is dependent on the technology applied, leading to the different prognostic expression patterns in multiple studies.12,16,31 Unfortunately, immunohistochemistry techniques, which are theoretical- ly easy to apply in a routine diagnostic setting, are mostly used to analyze small areas or even hotspots of B cells, making this approach prone to observer-dependent bias.17,30 Nevertheless, several groups previously noted that the expression of B-cell cluster genes was related to a favorable outcome in cHL.12,16,17,29,30 In contrast to previous findings, we did not identify a correlation between B-cell and macrophage content, which might also be related to the methodology used.
In view of the recent demonstration of variable pheno-
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