We read with interest the article by Provencio et al.(1) published in the April issue of the journal, reporting that low topoIIa1 expression is associated with inferior disease-free and overall survival in advanced HL.

This conclusion was drawn from a population of 42 patients with Ann Arbor stage II, III, IV, and at least two of the following: B symptoms; erythrocyte sedimentation rate ≥ 30 mm/h; and bulky mediastinal (>1/3) and/or peripheral mass (>10 cm). Among them, 6 did not achieve complete remission and 16 relapsed for a total of 22 failure events. Low topoIIa was defined as expression of this marker in <30% of CD30+ HRS cells and was associated with inferior prognosis. Furthermore, Provencio et al.(1) found a marginally significant association between low Ki-67 expression and worse outcome, although the inverse finding was expected (2, 3).

If topoIIa works as a proliferation marker in HL, then low topoIIa expression should be associated with better outcome, similarly to what observed for Ki-67 (2). In contrast, one could speculate that tumors with high topoIIa expression might provide a better target for topoisomerase inhibitors such as doxorubicin or epirubicin. Thus, low topoIIa expression might confer chemoresistance in HL. This hypothesis is compatible with the study of Provencio et al.(1).

We have examined the expression of topoIIa in a series of 59 patients with HL, 57 of whom were treated with current standard chemotherapy, including topoIIa inhibitors [ABVD or Epirubicin-bleomycin-vinblastine-imidazole carboxamide (4) or alternating nitrogen mustard-vincristine-procarbazine-prednisone/ABVD] with or without radiotherapy. Only 2 patients received nitrogen mustard-vincristine-procarbazine-prednisone plus radiotherapy. The median age of our patients was 31 years (range, 13–82 years), 44% were males, 41% had advanced stage (IIB, III, or IV), 24% B symptoms, 17% had ≥5 involved sites, 22% bulky mediastinal involvement, 26% anemia, 14% leucocytosis, 9% lymphocytopenia, 33% low albumin levels, 60% erythrocyte sedimentation rate >30 mm/h, and 32% elevated LDH. Classical HL was diagnosed in 55 of 59 patients (93%). Among them, 45 patients had nodular sclerosing histology (82%). The median follow-up of surviving patients was 55 months (range, 23–103 months). topoIIa expression was evaluated immunohistochemically using the monoclonal anti-topoIIa antibody KiS1 (Dako, Kalifronas, Greece) in a dilution of 1/50. We used the indirect streptavidine-biotin-hyperoxidase technique and a heat-mediated antigen retrieval method with a household microwave (5). Nuclear expression of topoIIa was found in a variable number of HRS cells in all patients. The median percentage of HRS cells expressing topoIIa was 60% (range, 13–93%; interquartile range, 42–74%). Among clinicopathologic and laboratory factors, only male gender correlated with higher topoIIa expression (P = 0.04). At a cutoff level of 30%, as used by Provencio et al.(1), there was a trend toward inferior outcome for patients with high topoIIa expression because none of the 8 patients with low expression failed primary therapy (5-year failure-free survival 100% versus 72% for topoIIa <30% versus ≥30%, p = 0.12, Fig. 1). The corresponding figures for failure-free survival using a cutoff of 40% were 92% versus 71% (p = 0.19). We observed a positive correlation between topoIIa expression and Ki-67, as estimated by MIB-1 staining (p = 0.007). Ki-67 expression had no impact on the outcome of this series of patients with HL.

In conclusion, low topoIIa expression had a borderline favorable effect on the outcome of patients with HL treated with standard chemotherapy including topoIIa inhibitors with or without radiotherapy. This observation, as well as the correlation between topoIIa and Ki-67 expression, favor the hypothesis that topoIIa plays a role as a proliferation marker in HL. This is in contrast to the data reported by Provencio et al.(6) and appears similar to the observations made in patients with non-Hodgkin’s lymphomas. The analysis of a substantially larger number of patients from our group is in progress to clarify the precise role of topoIIa and other cell cycle molecules in the prognosis of HL.

To whom request for reprints should be addressed, Gerasimos A. Pangalis, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 17 Aghiou Thoma Street, 11527 Athens, Greece. Phone: 0030210-7719744; Fax: 0030210-7770204; E-mail: pangalis@med.uoa.gr

1

The abbreviations used are: topoIIa, topoisomerase IIa; HL, Hodgkin’s lymphoma; HRS, Hodgkin-Reed-Sternberg; ABVD, Adriamycin-bleomycin-vinblastine-imidazole carboxamide.

Fig. 1.

Effect of topoIIa expression on failure-free survival of patients with HL, predominantly treated with ABVD and equivalent regimens.

Fig. 1.

Effect of topoIIa expression on failure-free survival of patients with HL, predominantly treated with ABVD and equivalent regimens.

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1
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