Correspondence

bcl-2 and Prognosis in Non-Small-Cell Lung Carcinoma

N Engl J Med 1994; 330:1757-1758June 16, 1994

Article

To the Editor:

Pezzella et al. (Sept. 2 issue)1 reported the detection of the bcl-2 protein in frozen tumor tissue from 25 of 122 patients with non-small-cell lung carcinoma. The hazard ratios for death were higher among the patients with bcl-2-negative tumors, and Cox regression analysis revealed that bcl-2 status was a stronger predictor of survival than lymph-node involvement in patients with squamous-cell carcinomas, particularly in those who were over 60 years of age.

We examined the relation of bcl-2 expression to the extent of apoptosis -- not reported by Pezzella et al. -- in non-small-cell lung carcinomas from 51 consecutive patients. We identified bcl-2 immunoreactivity in 13 of 51 tumors (13 of 41 squamous-cell carcinomas and none of 10 adenocarcinomas) by examining formalin-fixed, paraffin-embedded sections with an anti-bcl-2 antibody (Dako). The extent of apoptosis in the bcl-2-positive squamous-cell carcinomas did not differ from that in the bcl-2-negative tumors; the indexes for apoptosis2,3 in all 13 positive tumors and 24 of the 28 negative tumors were 3.8 percent or less. Data from clinical follow-up (mean, 459 days) were available for 37 of the 41 patients with squamous-cell carcinomas. Three of 17 living patients and 5 of 15 who died more than 30 days after surgery (those who died within 30 days after surgery were excluded) had bcl-2-positive tumors.

Our results confirm that the bcl-2 protein is abnormally expressed in a minority of patients with non-small-cell lung carcinomas. However, unlike Pezzella et al.,1 we found that patients with bcl-2-positive squamous-cell carcinomas did not have a better prognosis than those with bcl-2-negative tumors. Notably, in view of the rationale behind the investigation by Pezzella et al., we found no correlation between overexpression of bcl-2 and decreased apoptosis. Our finding is not surprising, because apoptosis is regulated by many genes, including other oncogenes and tumor-suppressor genes. Furthermore, the inhibitory effect of bcl-2 overexpression on apoptosis might be countered by factors that inhibit bcl-2 or by intracellular mechanisms regulated independently of bcl-24. For these reasons, we believe that there is no basis for the use of bcl-2 expression as a prognostic marker in non-small-cell lung carcinoma.

Eoin F. Gaffney, M.D.
Amanda J. O'Neill, B.Sc.
Marie J. Staunton, M.B., B.Ch.
St. James's Hospital, Dublin, 8, Ireland

4 References

1. 1

   Pezzella F, Turley H, Kuzu I, et al. bcl-2 Protein in non-small-cell lung carcinoma. N Engl J Med 1993;329:690-694
   Full Text | Web of Science | Medline

2. 2

   Leoncini L, Del Vecchio MT, Megha T, et al. Correlations between apoptotic and proliferative indices in malignant non-Hodgkin's lymphomas. Am J Pathol 1993;142:755-763
   Web of Science | Medline

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   Gaffney EF. The extent of apoptosis in different types of high grade prostatic carcinoma. Histopathology (in press).
   

4. 4

   Boise LH, Gonzalez-Garcia M, Postema CE, et al. bcl-x, a bcl-2-Related gene that functions as a dominant regulator of apoptotic cell death. Cell 1993;74:597-608
   CrossRef | Web of Science | Medline

Author/Editor Response

Dr. Pezzella replies:

To the Editor: Dr. Gaffney and colleagues raise two main issues concerning the role of bcl-2 in lung carcinoma: its validity as a prognostic marker and its role in inhibiting apoptosis.

As far as the first point is concerned, we clearly indicated that the confidence interval of the hazard ratio in our series was wide. If Gaffney et al. had read our paper carefully, they would have realized that their data (on 37 patients followed for a mean of 459 days) are fully compatible with our own results. They would also have realized that their series is too small to lead to any reliable conclusion. To address this very point, we are now investigating a series of 600 cases, which will provide data with a lower margin of error.

Their second observation, that the rate of apoptosis is the same among bcl-2-positive and bcl-2-negative tumors, is more stimulating. We agree that many factors affect apoptosis, as we have pointed out in a previous paper,1 but more research is needed to correlate the expression of genes regulating apoptosis with the actual occurrence of apoptosis. Gaffney et al. do not produce any evidence that the rate of apoptosis that they observed is higher than, lower than, or identical to that in normal tissue. It is therefore premature to conclude that bcl-2 is inhibited in these tumors; it could well be that apoptosis is increased in bcl-2-negative tumors.

We conclude, as stated in our article, that the investigation of a larger series is necessary to reach reliable conclusions about the role of bcl-2 in non-small-cell lung carcinoma. We are extending our own investigation, and we are looking forward to more complete results from Gaffney et al.

Francesco Pezzella, M.D.
European Institute of Oncology, 20141 Milan, Italy

1 References

1. 1

   Pezzella F, Morrison H, Jones M, et al. Immunohistochemical detection of p53 and bcl-2 protein in non-Hodgkin's lymphoma. Histopathology 1993;22:39-44
   CrossRef | Web of Science | Medline

Citing Articles (12)

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   Jun Young Hwang, Yoo Shin Choi, Sung Jun Park. (2009) Significance of Expression of Cell Cycle Related Proteins and Apoptosis Related Proteins in Follicular Adenoma and Follicular Carcinoma of Thyroid. Journal of the Korean Surgical Society 76:1, 7
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   Jiannong Li, Jean Viallet, Eric B. Haura. (2008) A small molecule pan-Bcl-2 family inhibitor, GX15-070, induces apoptosis and enhances cisplatin-induced apoptosis in non-small cell lung cancer cells. Cancer Chemotherapy and Pharmacology 61:3, 525-534
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   Eelco Fokkema, Wim Timens, Elisabeth G.E. de Vries, Steven de Jong, Vaclav Fidler, Coby Meijer, Harry J.M. Groen. (2006) Expression and prognostic implications of apoptosis-related proteins in locally unresectable non-small cell lung cancers. Lung Cancer 52:2, 241-247
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   Kwang Hyun Paik, Yeon Hee Park, Baek-Yeol Ryoo, Sung Hyun Yang, Jae Cheol Lee, Cheol Hyun Kim, Seung Seog Ki, Jung Min Kim, Myung Joon Park, Heui June Ahn, Won Choi, Jin Haeng Chung. (2006) Prognostic Value of Immunohistochemical Staining of p53, bcl-2, and Ki-67 in Small Cell Lung Cancer. Journal of Korean Medical Science 21:1, 35
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   J-L Pujol, O Molinier, W Ebert, J-P Daurès, F Barlesi, G Buccheri, M Paesmans, E Quoix, D Moro-Sibilot, M Szturmowicz, J-M Bréchot, T Muley, J Grenier. (2004) CYFRA 21-1 is a prognostic determinant in non-small-cell lung cancer: results of a meta-analysis in 2063 patients. British Journal of Cancer
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   Leos Kren, Jan Brazdil, Marketa Hermanova, Viktor N. Goncharuk, Bhaskar V. S. Kallakury, Prabhjot Kaur, Jeffrey S. Ross. (2004) Prognostic Significance of Anti-apoptosis Proteins Survivin and bcl-2 in Non-small Cell Lung Carcinomas. Applied Immunohistochemistry & Molecular Morphology44-49
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   Jinyoung Yoo, Ji Han Jung, Hyun Joo Choi, Seok Jin Kang, Chang Suk Kang. (2004) The Expression of c-myc, bcl-2 and p53 Proteins in Adenocarcinomas of Lung. Cancer Research and Treatment 36:2, 146
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   M Tomita, Y Matsuzaki, M Edagawa, T Shimizu, M Hara, T Onitsuka. (2003) Prognostic significance of bcl-2 expression in resected pN2 non-small cell lung cancer. European Journal of Surgical Oncology (EJSO) 29:8, 654-657
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   Michael Friedman, Jessica W. Lim, Ernie Manders, Adam D. Schaffner, Gary L. Kirshenbaum, Hasan M. Tanyeri, David D. Caldarelli, John S. Coon. (2001) Prognostic significance of Bcl-2 and p53 expression in advanced laryngeal squamous cell carcinoma. Head & Neck 23:4, 280-285
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    Young-Chul Kim, Kyung-Ok Park, Jeffrey A. Kern, Chang-Soo Park, Sung-Chul Lim, An-Soo Jang, Jae-Beom Yang. (1998) The interactive effect of Ras, HER2, P53 and Bcl-2 expression in predicting the survival of non-small cell lung cancer patients. Lung Cancer 22:3, 181-190
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    M.V Fleming, D.G Guinee, W.S Chu, A.N Freedman, N.E Caporaso, W.P Bennett, T.V Colby, H Tazelaar, S.L Abbondanzo, J Jett, P Pairolero, V Trastek, L.A Liotta, C.C Harris, W.D Travis. (1998) Bcl-2 immunohistochemistry in a surgical series of non-small cell lung cancer patients. Human Pathology 29:1, 60-64
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    Masahiko Higashiyama, Osamu Doi, Ken Kodama, Hideoki Yokouchi, Shoji Nakamori, Ryuhei Tateishi. (1997) bcl-2 oncoprotein in surgically resected nonsmall cell lung cancer: Possibly favorable prognostic factor in association with low incidence of distant metastasis. Journal of Surgical Oncology 64:1, 48-54
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