Aberrant T-cell antigen expression in classical Hodgkin lymphoma is associated with decreased event-free survival and overall survival

Abstract

Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) rarely express T-cell-associated antigens (TCA), but the clinical significance of this finding is uncertain. Fifty cHLs expressing any TCA on the HRS cells (TCA-cHL) were identified in two cohorts (National Cancer Institute, n = 38; Basel, n = 12). Diagnostic pathology data were examined in all cases with additional T-cell receptor γ rearrangements (TRG@) polymerase chain reaction (PCR) in a subset of cases. The outcome data were compared with a cohort of cHLs negative for TCA (n = 272). Primary end points examined were event-free survival (EFS) and overall survival (OS). The median age in the TCA-cHL group was 40 years (range, 10-85 years). Seventy percent presented in low stage (stage I/II) at presentation with nodular sclerosis (NS) histology predominating in 80% of cases. Among the TCA, CD4 and CD2 were most commonly expressed, seen in 80.4% and 77.4% of cases, respectively. TRG@ PCR was negative for clonal rearrangements in 29 of 31 cases. During a median follow up of 113 months, TCA expression predicted shorter OS (adjusted hazard ratio [HRadj] = 3.32 [95% confidence interval (CI): 1.61, 6.84]; P = .001) and EFS (HRadj = 2.55 [95% CI: 1.45, 4.49]; P = .001). TCA-cHL often display NS histology, lack T-cell genotype, and are independently associated with significantly shorter OS and EFS compared with TCA-negative cHLs.

Figure 1

cHL expressing TCAs. (A) Scattered HRS cells amid a background rich in histiocytes and lymphocytes. (B-D) The neoplastic cells express variable weak CD20 (CD20 immunoperoxidase, ×200), uniform CD30 (CD30 immunoperoxidase, ×100), and CD15 (CD15 immunoperoxidase, ×200 respectively. (E-G) CD3, CD4, and CD5 expression, respectively, on the HRS cells. There is membrane staining for CD3 (CD3 immunoperoxidase, ×400), CD4 (CD4 immunoperoxidase, ×400), and CD5, focally (CD5 immunoperoxidase, ×400); additionally, CD3 and CD4 show blob-like cytoplasmic staining.

Figure 2

Composite lymphoma comprising cHL and follicular lymphoma. TCA in cHL component. (A) Low-power view of the composite histologic components (H&E, ×100). (B,C) Higher-power view depicting morphologically distinct components; ie, follicular lymphoma grade 3 and cHL, respectively (H&E, ×200). (D-J) Various markers expressed within the HRS cell component with very weak and variable CD20 (D), PAX-5 (E), and BCL-6 (F) expression (immunoperoxidase, ×200, ×400, ×400). (G) These cells are EBER negative (in situ hybridization, ×400). (H-J) TCA expression in cHL component. Among the T-cell markers, there is strong CD3 (H), CD2 (I), and CD4 (J) expression on membrane of the HRS cells (immunoperoxidase, ×400, ×400, ×400). Notably, CD4 was variable in this case with adjoining scattered CD4-negative HRS cells, lending credence to the specificity of staining.

Figure 3

Summary of TCA expression. CD4 and CD2 were the most commonly expressed antigens. The order of frequency of TCA expression was CD4 (80.4%) > CD2 (77.4%) followed by CD3 (38%), CD7 (31%), CD5 (28.2%), and CD8 (7%).

Figure 4

Evaluation of staining for T-cell markers and TCA expression. (A) Indeterminate/negative staining showing lack of definitive membrane accentuation on the HRS cells in areas rosetted by T cells. Free area of HRS cell membrane (denoted with white arrow) opposite to areas of partial rosetting lacks distinctive membrane staining (CD4 immunoperoxidase, ×400). (B) Indeterminate staining showing complete rosetting by CD4-positive T cells without apparent accentuation on the HRS cells (CD4 immunoperoxidase, ×400). (C) Positive staining showing clusters of HRS cells with definitive but incomplete membrane staining. Typically, CD2 and CD7 stains showed areas with frequent incomplete staining patterns (CD2 immunoperoxidase, ×200). Cases with such staining patterns often showed more complete staining pattern in other areas of the same cases or displayed convincing positivity for another T-cell marker. (D) Definitive, complete circumferential membrane staining in clusters of HRS cells (CD2 immunoperoxidase, ×200). (E) Membrane and cytoplasmic Golgi staining for CD8 (immunoperoxidase, ×400). (F) Strong and diffuse cytoplasmic staining for perforin. This case was unique in that almost all HRS cells showed uniform, strong expression of perforin (perforin immunoperoxidase, ×400).

Figure 5

Details of immunohistochemical data on HRS cells in all 50 TCA-positive cases. In the IG@ PCR, NCI cases 21, 22, and 26 and Basel cases 11 and 12 were clonal. In the TRG@ PCR, only Basel cases 1 and 2 showed clonal TRG@. Green, positive; orange-red, negative; blank/white, missing/data not available.

Figure 6

TCA expression impacts (A) EFS and (B) OS.