Francesco Pezzella, Helen Turley, Isinzu Kuzu, Mohammed Fahim Tungekar, Michael S. Dunnill, Chris B. Pierce, Adrian Harris, Kevin C. Gatter, and David Y. Mason
Background The proto-oncogene bcl-2 encodes a protein that inhibitsprogrammed cell death (apoptosis). The protein is expressedin basal cells in normal human epithelium, but no data are availableon the frequency or clinical importance of its expression incarcinoma. We studied bcl-2 expression in patients with non-small-celllung carcinoma and correlated this phenomenon with survival.
Methods Immunochemical analysis with a monoclonal antibody specificfor bcl-2 was used to detect the protein in tumor samples from122 patients undergoing surgery for squamous-cell carcinoma(80 patients) or adenocarcinoma (42 patients). The possibilitythat bcl-2 expression correlated with survival was investigatedwith use of the log-rank test, hazard ratios, and their confidenceintervals.
Results We detected bcl-2 protein in 25 percent of squamous-cellcarcinomas (20 of 80) and 12 percent of adenocarcinomas (5 of42). In adjacent normal respiratory epithelium, bcl-2 was expressedonly in basal cells. Survival at five years was higher amongpatients with bcl-2-positive tumors, both in the group as awhole (P<0.1) and in the group with squamous-cell carcinoma(P<0.02). Patients 60 years of age or older who had bcl-2-positivetumors had the best prognoses, both in the group as a whole(P<0.02) and in the group with squamous-cell carcinoma (P<0.01).
Conclusions The proto-oncogene bcl-2 is abnormally expressedin some lung carcinomas, and its expression may have prognosticimportance.
The bcl-2 proto-oncogene is involved in the 14;18 translocation,1a chromosomal abnormality present in 70 percent of follicularlymphomas and 20 percent of diffuse B-cell lymphomas2,3. Inthis translocation4 the bcl-2 gene is juxtaposed with the immunoglobulinheavy-chain gene on chromosome 14 and is brought under the controlof the promoter of this gene. In consequence, abnormally highlevels of bcl-2 protein are produced1,5,6. This protein protectscells from programmed cell death (apoptosis),7 as shown by thesurvival advantage of cells in which expression of the genehas been artificially induced (e.g., by the creation of transgenicmice or by cell transfection)8,9.
Korsmeyer has recently proposed10 that bcl-2 is a member ofa new category of oncogenes that is not involved in influencingcell proliferation but is involved in regulating cell death.So far, it is the only gene belonging to this category thathas been identified. It has an oncogenic effect because of again of function (i.e., expression of the protein when it shouldnot be present) and appears to lead to neoplastic growth ata rate slower than that of growth induced by oncogenes directlyaffecting cell proliferation11.
Hockenbery et al.11 have reported that bcl-2 is expressed notonly in lymphoid cells but also in several epithelial tissues-- e.g., skin and intestine -- where it is detectable in basalcells but not in more superficial, differentiated cells. Ithas been suggested that this pattern of expression assists thesurvival of stem cells while preventing the overaccumulationof differentiated cells10. This implies that if bcl-2 expressionwere to persist in epithelial cells in which the protein shouldno longer be present, such cells would accumulate abnormally.This would provide a potential mechanism for neoplastic-cellgrowth, but to the best of our knowledge, no studies of bcl-2expression in carcinoma have been performed. To address thisquestion we studied lung cancer, which accounts for approximatelyone quarter of all deaths due to cancer in industrialized countries12.We evaluated a series of 122 patients with non-small-cell carcinomasof the lung for whom detailed information on long-term follow-upwas available. We intended to establish whether bcl-2 proteinis expressed in these tumors and to study its relation to survival.
Methods
Tissue Samples
Freshly frozen samples of lung specimens from 122 patients undergoingresection for primary lung cancer were obtained from diagnostichistopathology laboratories at the John Radcliffe Hospital,Oxford. Frozen samples were stored at -70 °C until studied.
Patients
Table 1 shows the characteristics of the 122 patients in whombcl-2 expression was studied, and Table 2 those of the 115 patientsin whom survival was analyzed according to their status forbcl-2. All patients underwent surgery if their tumor was apparentlylimited to one lobe, with no evidence of metastasis, and theirresidual lung function was good. The pathological stages ofthe tumors were T1, T2, N0, and N1 of the TNM classification(Table 1 and Table 2), corresponding to stages I and II of theclassification used by the American Joint Committee for CancerStaging and Reporting13 and stages I and II of the InternationalStaging System for Lung Tumours14. Although clinical follow-upwas available for all patients, seven who died within 30 daysafter surgery (perioperative mortality) were excluded from survivalanalysis. The 115 patients included had no other form of cancer.No chemotherapy or radiotherapy was given before the surgery,which represented the sole treatment in most patients. Localradiotherapy was given at later dates to control symptoms infour patients with squamous-cell carcinoma and five with adenocarcinoma.Chemotherapy was given to one patient with adenocarcinoma.
Table 1. Characteristics of 122 Patients Undergoing Resection for Non-Small-Cell Lung Carcinoma, According to Type of Cancer and Status for bcl-2 Expression.
Table 2. Characteristics of 115 Patients with Non-Small-Cell Lung Carcinoma in Whom Survival Was Studied in Relation to bcl-2 Expression.
Follow-up of the 115 patients included in the survival analysisranged from 50 to 2282 days (76 months), with a median of 1033days (34 months). Fifty-two patients died during follow-up;the 63 alive at the time of study were followed for 50 to 2282days (76 months), with a median of 1448 days (48 months). Statisticalanalysis was performed for the patients as a whole and for thegroup with squamous-cell carcinoma, but not for the group withadenocarcinoma since bcl-2 was expressed in only five patientsin this group.
Histopathological and Immunohistologic Examination
Diagnosis was based on conventional morphologic examinationof paraffin-embedded specimens. Tumors were classified as squamous-cellcarcinomas or adenocarcinomas according to the predominant celltype. Staining was performed on cryostat sections with the alkalinephosphatase:anti-alkaline phosphatase procedure as previouslydescribed,15 with use of a monoclonal antibody specific forbcl-2 (clone 100)16. Staining without this antibody was routinelyperformed as a negative control procedure.
Statistical Analysis
Survival was measured in days from the date of surgery. Patientswere grouped according to their age at the time of the surgery,as being either less than 60 years old or 60 years old or older,as described in previous studies of lung cancer17,18. Actuarialsurvival curves were plotted with the method of Kaplan and Meier19.Two-sided P values were determined with the log-rank test,20and the death hazard ratio with a 95 percent confidence intervalwas calculated as described by Machin and Gardner21. The associationbetween bcl-2 expression and the grade of tumor differentiation,the T stage, and the N stage was investigated by a frequencytable22. The homogeneity of age in different groups was assessedby calculating the value of F with one-way analysis of variance23.Cox regression analysis was performed with use of the SAS statisticalpackage (SAS Institute, Cary, N.C.).
Results
Immunostaining for bcl-2 Protein
Of the 122 patients studied (80 with squamous-cell carcinomasand 42 with adenocarcinomas), 25 (20 percent) were found tohave bcl-2 protein (Figure 1A). The findings are presented accordingto the histologic type of carcinoma in Table 1. In areas ofnormal epithelium adjacent to the tumor, basal cells showedpositive staining for bcl-2 but the more differentiated columnarcells remained negative (Figure 1B).
Figure 1. Immunostaining of Lung Tissue with a Monoclonal Antibody Specific for bcl-2 (Alkaline Phosphatase:Anti-Alkaline Phosphatase Method, with Hematoxylin Counterstaining).
Panel A shows a squamous-cell carcinoma expressing bcl-2 protein (pink staining), with unstained connective tissue in the lower part of the panel. Panel B shows normal respiratory epithelium: the basal cells are positive for bcl-2 (arrows), whereas differentiated columnar cells are negative.
Survival and Expression of bcl-2
The study results are summarized in Table 3. There was no associationof bcl-2 expression with the grade of tumor differentiation(P>0.2), the T stage (P>0.2), or the N stage (P>0.2),either among the patients as a whole or in the group with squamous-cellcarcinoma. The distribution of ages was homogeneous when agewas analyzed independently of bcl-2 status (Table 2). Overall,there was only a slight difference in survival between the patientswith bcl-2-negative tumors and those with bcl-2-positive tumors(P<0.1) (Figure 2). Cox regression analysis (Table 4) confirmedthat this difference in survival was not significant and thatthe only significant prognostic factor was the involvement ofregional lymph nodes by tumor. In the patients with bcl-2-negativetumors, the hazard ratio was 1.92 (95 percent confidence interval,1.08 to 3.6); in those with bcl-2-negative tumors who were 60years old or older, the ratio was higher -- 2.59 (95 percentconfidence interval, 1.26 to 5.31; P<0.02) (Figure 2). Nocorrelation between the expression of bcl-2 and survival wasevident in the group of younger patients (Table 3).
Table 4. Value of Six Variables in Predicting Survival in 115 Patients with Non-Small-Cell Lung Carcinoma, According to Cox Regression Analysis.
When the patients with squamous-cell carcinoma were studiedseparately, the association between bcl-2 expression and survivalwas more evident (P<0.05). Cox regression analysis (Table 5)showed that a patient's status for bcl-2 had the lowest Pvalue (P = 0.010) and was a better predictor of survival thanstatus for regional-node involvement (P = 0.033). In the patients60 years old or older, the association was also significant(P<0.01) (Figure 3 and Table 3); no evidence of such an associationwas found in the younger patients. There were too few patientswith bcl-2-positive tumors (five patients) in the group withadenocarcinoma to allow statistical analysis of this diagnosticgroup.
Figure 3. Survival of Patients with Squamous-Cell Lung Carcinoma and the Subgroup 60 Years Old or Older, According to Status for bcl-2 Protein.
Discussion
Immunostaining of tumors from patients undergoing surgical resectionfor lung cancer revealed bcl-2 expression in both squamous-cellcarcinomas and adenocarcinomas. Both these types of tumors arebelieved to originate from the respiratory epithelium, althoughthe pattern of expression of bcl-2 protein is quite differentfrom that seen in normal bronchial mucosa (and indeed in anyother epithelium examined),11 in which the basal cells stainfor bcl-2 but well-differentiated cells do not. This suggeststhat the homogeneous staining in bcl-2-positive tumors reflectsa persistence of bcl-2 expression that was not suppressed asthe neoplastic cell differentiated.
The cause of this abnormal expression of bcl-2 in lung tumorsis unknown. The classic cause of overexpression of bcl-2 --the 14;18 translocation -- has not been detected in lung carcinoma,nor have other abnormalities of chromosome 18. However, it isworth noting that since this protein can be overexpressed insome follicular lymphomas without the 14;18 translocation,24this cytogenetic abnormality is not the sole cause of bcl-2deregulation in neoplastic cells. The finding that the proteinis absent or weakly expressed in proliferating lymphocytes,16although bcl-2 messenger RNA increases in peripheral-blood lymphocytesafter in vitro stimulation,25 suggests post-transcriptionalregulation as a possible physiologic mechanism controlling theexpression of bcl-2. If this is so, alterations in the controlof messenger RNA translation could lead to aberrant accumulationof bcl-2 protein.
Two important questions follow the demonstration of an abnormallyexpressed antigen in tumors: what value may the antigen haveas a diagnostic marker, and how is it related to survival26?The finding that bcl-2 is absent in normal well-differentiatedepithelial cells but present in a number of lung carcinomassuggests that its detection in differentiated epithelial cellscould be an indicator of malignancy. However, the value of bcl-2detection as a diagnostic tool remains uncertain, and beforeconsidering its expression in differentiated epithelial cellsto be a marker of this sort, one must know whether bcl-2 expressionoccurs not only in fully transformed neoplastic cells but alsooccasionally in dysplastic and metaplastic cells.
We propose that expression of bcl-2 protein may be a new prognosticmarker in non-small-cell carcinoma of the lung, in additionto blood-group antigen A,17 blood-group-antigen-related carbohydrates,18and (only in adenocarcinoma) K-ras oncogene mutation27. In ourstudy, the death hazard ratio was higher in patients with bcl-2-negativetumors, whether we evaluated all patients or only those withsquamous-cell carcinoma, and the log-rank tests showed thatbcl-2 expression was significantly associated with survivalin the group with squamous-cell tumors. Furthermore, Cox regressionanalysis revealed that bcl-2 status was a stronger predictorof survival than status for lymph-node involvement in the patientswith squamous-cell carcinomas, all of whom had disease no furtheradvanced than stage T2N1. Analysis according to age revealedthat this result appeared to be due to a better prognosis amongpatients 60 years old or older with bcl-2-positive tumors. Becauseof the relatively small number of patients studied, the confidenceintervals for the death hazard ratios were wide, indicatingthat these data must be interpreted with caution21,28 and requireconfirmation by study of a larger series. Nevertheless, whenpatients 60 years old or older were considered, the 95 percentconfidence interval indicated that the true value of the deathhazard ratio at five years would very likely be higher in patientswith bcl-2-negative tumors. This result strongly suggests thehypothesis, supported by the log-rank analysis, that these patientswith bcl-2-positive tumors do have a better clinical outcome,and should prompt further investigation of bcl-2 as a prognosticmarker in lung cancer. Should carcinomas that might otherwisebe regarded as inoperable be reconsidered for surgical treatmentif biopsy shows them to be positive for bcl-2? To answer thisquestion, we think that the analysis of bcl-2 expression inbiopsy specimens from patients whose tumors are classified asinoperable at present, and the correlation of expression withsurvival, would be of great value.
Why bcl-2 expression appears to be associated with less aggressivetumor behavior remains to be clarified. However, it is knownthat bcl-2 promotes cell survival even when the rate of cellproliferation is not high, providing a growth advantage thatmay eventually lead to neoplastic transformation9. It has beensuggested that in clones in which a low mitotic rate is offsetby bcl-2 expression, the rate of acquiring complementary defectsis slower than in clones with a high mitotic rate8. A growthadvantage due to cellular survival with a low mitotic rate,together with slower acquisition of additional genetic defects,could explain the indolent progression of follicular lymphoma,in which bcl-2 expression is a frequent primary aberration8,9.Korsmeyer has recently suggested that alterations of a genesuch as bcl-2, which controls cell death, could be a frequentprimary aberration not limited to follicular lymphoma but occurringin other types of neoplasms10. Our observation of a group ofbcl-2-positive lung cancers with relatively slow progressionsuggests that perhaps in these tumors, bcl-2 expression actsas an initial oncogene, as in follicular lymphomas, leadingto less aggressive growth of tumors.
We conclude that bcl-2 is abnormally expressed in some non-small-celllung carcinomas. Further investigations are called for to elucidateits possible use as a diagnostic and prognostic marker in themanagement of these tumors.
Supported by the Leukaemia Research Fund, the Imperial CancerResearch Fund, and the Cancer Research Campaign. Dr. Pezzellais a Leukaemia Research Fund research fellow.
We are indebted to Dr. Raymond G. Flood for his statisticaladvice and critical review of the manuscript; to Mrs. MargaretJones and Mr. Geoffrey Richardson for their technical assistance;and to the cardiothoracic surgeons at Oxford, Mr. A. Gunning,Mr. S. Westaby, and Mr. R. Pillai, for their continuing assistancein providing specimens.
Source Information
From the Leukaemia Research Fund Immunodiagnostics Unit (F.P., D.Y.M.), the Nuffield Department of Pathology (H.T., I.K., M.F.T., M.S.D., K.C.G.), the University Data Centre (C.B.P.), and the Molecular Oncology Laboratory (Imperial Cancer Research Fund) (A.H.), John Radcliffe Hospital, Oxford, United Kingdom.
Address reprint requests to Dr. Pezzella at the Leukaemia Research Fund Immunodiagnostics Unit, Level 1, Maternity Block, John Radcliffe Hospital, OX3 9DU, Oxford, United Kingdom.
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