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Blood, 1 July 2002, Vol. 100, No. 1, pp. 36-42
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
High numbers of active caspase 3-positive
Reed-Sternberg cells in pretreatment biopsy specimens of patients with
Hodgkin disease predict favorable clinical outcome
Danny F. Dukers,
Chris J. L. M. Meijer,
Rosita L. ten
Berge,
Wim Vos,
Gert J. Ossenkoppele, and
Joost
J. Oudejans
From the Departments of Pathology and Haematology, VU
Medical Centre Amsterdam, The Netherlands.
In vitro studies suggest that resistance to the apoptosis-inducing
effect of chemotherapy might explain poor responses to therapy in fatal
instances of Hodgkin disease (HD). Execution of apoptosis depends on
proper functioning of effector caspases, in particular caspase 3, which
is activated on the induction of apoptosis through either the
stress-induced pathway or the death receptor-mediated pathway. Thus,
high levels of caspase 3 activation should reflect proper functioning
of one or both identified apoptosis pathways, resulting in
chemotherapy-sensitive neoplastic cells and thus a favorable clinical
response to chemotherapy. We tested this hypothesis by
quantifying active caspase 3-positive tumor cells in primary biopsy
specimens of HD and compared these numbers to clinical outcomes. Using
an immunohistochemical assay, activation of caspase 3 was detected
in 0% to 13% of neoplastic cells. High numbers of active caspase
3-positive tumor cells (5% or more) correlated with excellent
clinical prognosis; 0 of 22 patients with 5% or more active caspase
3-positive cells died compared with 11 of 41 patients with less than
5% positive cells (P = .007). Proper functioning of
active caspase 3 was demonstrated by the detection of one of its
cleaved substrates, PARP-1/p89, in similar percentages of
neoplastic cells. High levels of active caspase 3-positive neoplastic
cells were associated with the expression of p53 and its downstream
effector molecule p21, suggesting proper functioning of the
stress-induced apoptosis pathway. In conclusion, high numbers of
active caspase 3-positive neoplastic cells predict a highly favorable
clinical outcome in HD patients, supporting the notion that an (at
least partially) intact apoptosis cascade is essential for the cell
killing effect of chemotherapy.
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