We investigated the clinical significance of sCD30 and other biomarkers in 116 patients with CD30CLPD and 96 patients with early MF. Considering that CD30 and CD25 are expressed by the atypical cells in skin lesions of LyP, particularly histologic subtypes A and C, and pcALCL (El Shabrawi-Caelen et al., 2004
; Willemze and Beljaards, 1993
; Willemze et al., 2005
) it was not surprising that serum levels of these markers in CD30CLPD patients were significantly higher than in CD30-low ISD cases. We also found increased sCD30 and sCD25 levels were associated with worse overall and disease-related survivals, suggesting the levels might reflect the number of neoplastic cells in the skin and identify patients with an increased risk for disease progression. In a Cox model that included advanced age (≥ 60 years), increased sCD30 levels were a better predictor of prognosis than either sCD25 or histopathologic classification of CD30CLPD lesions.
In this regard, Bekkenk reported their experience with 110 Dutch patients with LyP and 79 with pcALCL. In their study, 2/118 (1.7%) of LyP patients and 4/79 (5.1%) with pcALCL died as a result of lymphoma compared to 3/103 (2.9%) LyP patients and 2/13 (15.4%) pALCL in our study. Death rates among LyP-A or B, LyP-C and pcALCL in Bekkenk’s study were not significantly different (P = 0.536, χ2 test) whereas the difference was significant in our study (P = 0.033). In addition, they did not identify any clinical or histopathologic finding that correlated significantly with tumor progression by univariate analysis including age or CD30CLPD subtype. Although the median ages for LyP and pcALCL at the time of study entry for each patient population was nearly identical, the median follow up times were considerably longer for our patients (118 months for LyP and 114 months for pcALCL for our patients compared to 77 months for LyP and 61 months for pcALCL for Bekkenk’s patients). Because disease progression and the development of systemic involvement often requires years to occur, (Bekkenk et al., 2000
; Gruber et al., 2006
) this could account for the difference in the observed death rates for the two patient populations.
Our study showed sCD30 and sCD25 are increased in early MF and high sCD30 but not sCD25 levels correlated with worse overall and disease-related survival in a Cox model that included advanced age. The risk of death from progressive disease in this MF cohort was quite low (~ 4%), but similar to what other groups have reported. (Kim et al., 1996
; van Doorn et al., 2000
) Edinger reported that frequent dermal CD30+ cells were an independent adverse prognostic factor in non-transformed MF. (Edinger et al., 2009
) Because we studied only CD30-low early MF cases, we could not confirm the prognostic significance of CD30+ cell numbers in skin lesions of the MF cohort. It is likely that increased sCD30 levels in early MF cases are derived in part from CD30-expressing non-neoplastic cells, and the observation that sCD30 values did not correlate with clinical response suggests skin lesions are not the only source of sCD30 in MF.
Our study showed a significantly positive correlation between sCD30 levels and sCD25, IL-6, and IL-8 as well as sCD40L, suggesting that CD30+ cells are secreting these proteins, but not IL-4 nor other Th2 cytokines. In vitro studies confirmed that sCD30, sCD25, IL-6 and to a lesser degree IL-8, but not CD40L were secreted by CD30CLPD-derived cells. Absence of IL-4 and IL-5 in CD30CLPD-derived supernatants and lack of concordance between sCD30 and IL-4 or IL-5 levels in patient sera suggest that CD30+ neoplastic cells do not closely resemble Th2 cells.
Despite the variable histology between individual lesions of patients with CD30CLPD, we found significant correlation between sCD30 levels and histopathologic subtypes in our patients, possibly due to selection of clinically advanced lesions for biopsy. If sCD30 were secreted by neoplastic cells in vivo, one might expect serum levels to reflect the total number of CD30+ neoplastic cells in skin infiltrates which depend on (1) the number of lesions, and (2) the average density of CD30+ cells. Neither variable can reliably be determined in clinical practice, suggesting the need for a serologic biomarker.
Our studies indicate that IL-6 is increased in CD30CLPD cases and in Mac2A cells which have a 20-fold amplification of IL-6 gene expression compared to Mac1 cells from earlier disease.(Li et al., 2001
) Several studies indicate CD30+ neoplastic cells from systemic ALCL secrete IL-6 and that IL-6 can act as an autocrine growth factor.(Siebert et al., 2007
) Therefore, high serum IL-6 levels may portend a poor prognosis, and in our study, an above normal level of IL-6 identified CD30CLPD patients with a worse survival from disease-related death but not overall death as the event. However, the number of patients with progressive CD30CLPD was small and further studies are required to confirm this finding.
Our observation that IL-8 serum levels correlate significantly with sCD30 levels in both CD30CLPD (rho = 0.322) and early MF (rho = 0.435), and that 35% of CD30-expressing tumor controls had elevated IL-8 values and absolute values significantly higher than other groups suggests that IL-8 is secreted by CD30+ neoplastic cells. Furthermore small amounts of IL-8 were secreted by CD30CLPD-derived cells in vitro. A previous study by one of the authors (MEK) revealed tumor cell secretion of IL-8 and increased serum levels in cases of neutrophil-rich pcALCL. (Burg et al., 2003
One hypothesis to explain the correlation between increased sCD30 levels and adverse prognosis is that high sCD30 (and sCD25) levels reflect a general state of immune activation, perhaps to a persistent antigen, that predisposes susceptible individuals to development and/or progression of CD30CLPD and MF. (Chechlinska et al., 2010
); (Vendrame and Martinez-Maza, 2011
); (Burg et al., 2001
) A possible mechanism is that cross-linking of cell surface CD30 causes up-regulation of NF-kB, (Levi et al., 2000
) which activates anti-apoptotic C-FLICE in cutaneous ALCL cells (Braun et al., 2010
). A similar mechanism may be operative in MF in which NF-kB, a pro-survival transcription factor, is constitutively expressed (Izban et al., 2000
A prospective study is needed to confirm or refute our hypothesis that patients with CD30CLPD and above normal serum values for sCD30, sCD25 or IL-6 (and early MF patients with high sCD30 levels) are at increased risk for disease progression or development of an associated lymphoma. Accordingly, we suggest that sCD30, sCD25 and IL-6 be measured as part of the baseline evaluation and if any biomarker is increased, such patients should undergo staging procedures (e.g. PET scan) and be more closely monitored by clinical examinations than might otherwise be done. In this context, it is important to exclude other possible explanations for a rise in sCD30 or sCD25 such as autoimmune diseases. (Kadin, 2000
) We also suggest biomarker levels be measured at regular intervals (6 to 12 months) to determine if an increased baseline value persists or a value changes from normal to persistently high during follow up. This might prompt repeat staging procedures.
Our observations on a small number of patients (eight) suggest that there was an inconstant correlation between observed clinical responses and serum levels of sCD30 and sCD25 before and after treatment. Nevertheless, persistent elevation of sCD30, sCD25 or IL-6 in the face of a favorable treatment response might identify patients at risk for poor outcome. Conceivably, a high baseline sCD30 could even be a harbinger of B-lymphoproliferative disorders known to be associated with MF (Barzilai et al., 2006
; Purdue et al., 2009
)(Hallermann et al., 2007
; Herro et al., 2009