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In Reply:

Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

We would like to thank Spector et al for their comments on our recent paper,¹ and for giving us the opportunity to discuss further some important points of our report. Their remarks focus on the methodologic limitations of our study, especially with respect to the prognostic role of p53 expression in Hodgkin's lymphoma (HL). Several matters arise from these comments.

We fully agree about the convenience of standardizing immunohistochemical techniques used for clinical diagnosis, which is still an open issue. As Spector et al indicate in their letter, there is no consensus about the optimal immunohistochemical method or the appropriate thresholds for assessing p53 status at present.

Our study shows that the selected p53 immunostaining threshold (80% of tumoral cells, which corresponds to strong staining of a majority of tumoral cells), probably reflects a biologic event that could be of clinical relevance.

Since p53 nuclear overexpression is a well-known phenomenon in HL, and intermediate levels of expression are usually unrelated to the presence of gene alterations,² we have chosen this high threshold of p53 expression, which is similar to that found to reflect p53 mutations in non-HL³ and HL.⁴ Taking the opportunity provided by this letter, we have reviewed the scientific contributions related with p53 staining in HL samples. The different studies that have found some prognostic significance of the overexpression of the p53 protein are those that employ higher thresholds (usually far higher than 10%) and/or include a large number of HL samples.^5-9 These differences could explain the different results reported by other groups, including those described by Spector et al.

Future work in identifying prognostic factors in HL should take into account the difficulty of comparing different HL series due to the many variables that need to be considered: number of cases included, stages, treatment modalities, geographical differences, presence of the Epstein-Barr virus, HIV status, and so on. Only meticulous stratification of patients will permit a clear interpretation of results.

The aim of our work is just to demonstrate that biologic markers, in conjunction with other standard clinical variables, can be used for clinical prognostication in HL patients. Further research will be needed to refine these models. Ideally, these studies should involve large numbers of specimens derived from patients treated in clinical trials with identical regimens and follow-up.

Author's Disclosures of Potential Conflicts of Interest

The author has indicated no potential conflicts of interest.

REFERENCES

1. Montalban C, Garcia JF, Abraira V, et al: Influence of biologic markers on the outcome of Hodgkin's lymphoma: A study by the Spanish Hodgkin's Lymphoma Study Group. J Clin Oncol 22:1664-1673, 2004[Abstract/Free Full Text]

2. Elenitoba-Johnson KS, Medeiros LJ, Khorsand J, et al: p53 expression in Reed-Sternberg cells does not correlate with gene mutations in Hodgkin's disease. Am J Clin Pathol 106:728-738, 1996[Medline]

3. Mansukhani MM, Osborne BM, Zhong J, et al: The pattern of p53 and p21WAF1/CIP1 immunoreactivity in non-Hodgkin's lymphomas predicts p53 gene status. Diagn Mol Pathol 6:222-228, 1997[CrossRef][Medline]

4. Maggio EM, Stekelenburg E, Van den Berg A, et al: TP53 gene mutations in Hodgkin lymphoma are infrequent and not associated with absence of Epstein-Barr virus. Int J Cancer 94:60-66, 2001[CrossRef][Medline]

5. Garcia JF, Camacho FI, Morente M, et al: Hodgkin and Reed-Sternberg cells harbor alterations in the major tumor suppressor pathways and cell-cycle checkpoints: Analyses using tissue microarrays. Blood 101:681-689, 2003[Abstract/Free Full Text]

6. Amini RM, Enblad G, Engstrom P, et al: Relapsed Hodgkin's lymphoma: Immunostaining patterns in relation to survival. Leuk Lymphoma 43:1253-1260, 2002[CrossRef][Medline]

7. Smolewski P, Robak T, Krykowski E, et al: Prognostic factors in Hodgkin's disease: Multivariate analysis of 327 patients from a single institution. Clin Cancer Res 6:1150-1160, 2000[Abstract/Free Full Text]

8. Smolewski P, Niewiadomska H, Blonski JZ, et al: Expression of proliferating cell nuclear antigen (PCNA) and p53, bcl-2 or C-erbB-2 proteins on Reed-Sternberg cells: Prognostic significance in Hodgkin's disease. Neoplasma 45:140-147, 1998[Medline]

9. Naresh KN, O'Conor GT, Soman CS, et al: A study of p53 protein, proliferating cell nuclear antigen, and p21 in Hodgkin's disease at presentation and relapse. Hum Pathol 28:549-555, 1997[CrossRef][Medline]

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Related Correspondence

• p53 Expression As a Prognostic Indicator in Hodgkin's Lymphoma
  Nelson Spector, Cristiane B. Milito, Irene Biasoli, and José Carlos Morais
  JCO 2005 23: 3158-3159 [Full Text]

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