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Circulating IgE levels in patients with bronchial carcinoma
Br. ft. Dis. Chest (1981) 75, 77
C I R C U L A T I N G IgE LEVELS IN PATIENTS W I T H BRONCHIAL CARCINOMA THORSTEIN BLONDAL AND ENN N6U
Department of Lung Medicine, University of Uppsala, Sweden
SummaFy Serum I g E m e a s u r e m e n t s in 107 patients with bronchial carcinoma revealed statistically significant elevations w h e n c o m p a r e d to a control population. S e r u m I g E elevation was seen in 21.5% of the sample (23 of 107) and in all histological types at all clinical stages of the disease. It appears to occur early in the disease or possibly before the d e v e l o p m e n t of the carcinoma.
INTRODUCTION In recent years several reports have appeared on s e r u m levels of I g E in p r i m a r y bronchial carcinoma. Some authors have f o u n d raised levels of I g E ( W a l d m a n et al. 1974; Lfithgens et al. 1977) while others did not find any differences f r o m the levels in n o r m a l controls (Winters & H e i n e r 1976; Pauwell & Straeten 1975; Serrou & D u b o i s 1975). T o the best of our knowledge the following s t u d y of I g E in bronchial carcinoma is the first in which measurements have been carried out in an unselected population of patients.
Methods Serum samples were collected from 107 patients during a prospective epidemiological survey of primary bronchial carcinoma in the County of Uppsala in Sweden during the years 1974-6 (N~u et al. 1979). The clinicoanatomical stages (Feinstein 1968) of the disease were grouped as follows: A. Limited disease with local metastases (clinicoanatomical stages 1-3). B. Advanced disease with distant metastases (clinicoanatomical stage 4). The tumours were classified according to the W H O histopathological classification (Kreyberg 1967) as epidermoid carcinoma (WHO I), small cell anaplastic (WHO II), adenocarcinoma (WHO III) and large cell carcinoma (WHO IV). There were no tumours belonging to the group of combined epidermoid and adenocarcinoma (WHO V). The IgE determinations were performed at the Blood Centre of the University Hospital in Uppsala. The serum IgE concentrations were measured by the paper disc R I S T (PRIST) method (Johansson et al. 1976). For comparisons a population of 175 adults was used. These persons were selected from participants in a health survey in the county of Uppsala. Individuals with a history of asthma, allergic rhinitis, urticaria or atopic eczema were excluded. In this control material there were no significant changes in the IgE concentrations with respect to sex or age. 114 patients with carcinoma were detected in the survey. Seven patients suffering from the allergic diseases mentioned above were eliminated from the study, leaving a final total of 107 individuals.
78
Thorstein Bldndal and Enn NSu
As s e r u m IgE c o n c e n t r a t i o n s are n o t d i s t r i b u t e d in a n o r m a l m a n n e r the log10 of the i m m u n o globulin c o n c e n t r a t i o n was used in the statistical analyses w h i c h were p e r f e r m e d b y S t u d e n t ' s t-test and the X2 test.
RESULTS
Of the 107 patients with bronchial carcinoma, 84 were male. Fig. 1 shows serum IgE concentrations of patients with carcinoma; 24 of the values lie outside the 2 SD confidence limits of the control group, 23 above and one below. The increase in serum IgE levels with age is in contrast to the lack of significant trends
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Age in years Fig. 1. Serum IgE levels in patients with carcinoma plotted against age. The difference in level between men and women is not significant (P<0.1). Note the male preponderance among the patients as a whole (78.5%) as well as amongst those with elevated serum IgE levels (87%). Dotted lines represent the 95 % confidence limits of results from the control group
with age in the control population. The geometric mean IgE concentrations are significantly elevated above normal in patients with carcinoma (Table I) and in each of the four histological groups (Table II). The difference is largest in the group with small cell carcinoma (43.5 ku/litre) and smallest in the adenocarcinoma group (16 kv/litre). Analysis of the results according to clinicoanatomical stage showed no statistically significant differences (Table III). Tumours detected by mass miniature radiography constitute 24 of 107 (22.4%). The geometric mean value of the serum IgE in these patients was 47.3 kv/litre compared to 43.3 ku/litre in the remainder of the patients. This difference is not statistically significant at the 95% confidence level.
I g E Levels in Bronchial Carcinoma
79
Table I. Serum IgE concentrations in 107 patients with bronchial carcinoma and in 175 controls
n Bronchial carcinoma Controls P
107 175
~ 44.2 14 < 0.001
+ 2 SD
Range
2.3-856.7 1.6-122
1-4700 0.1-133
Data presented as geometric mean with 95 % interval. Table II. Serum IgE concentrations in four histological groups of bronchial carcinoma compared to controls Histological group
n
,~
_ 2 SD
Epidermoid (I) Small cell (II) Adenocarcinoma (III) Large cell (IV)
51 21 31 4
48.0 57.5 30.0 75.0
1.9-1215.1 2.2-1510.9 3.0-295.7 12.8-438.1
Controls
175
14
1.6-122
The difference between the geometric mean values in each carcinoma group and that of the control group is statistically significant (P less than 0.001 for groups I, II and I I I and less than 0.01 for group IV). Table I l L Serum IgE levels in patients with limited disease (clinicoanatomical stages 1-3) compared to the serum IgE levels in patients with widespread disease (clinicoanatomical stage 4) Histological group
Epidermoid Small cell Adenocarcinoma Large cell
Clinicoanatomical stage
n
x
1-3 4 1-3 4 1-3 4 1-4
38 13 6 15 ' 22 9 4
50.5 41.4 26.3 78.6 36,5 18.6 75.0
The difference between the geometric mean values within each histological group (limited disease vs advanced) was not statistically significant in any group.
DISCUSSION Our study has c o n f i r m e d p r e v i o u s r e p o r t s of r a i s e d s e r u m IgE levels in b r o n c h i a l carcinoma. Does this e l e v a t i o n o c c u r b e f o r e or after d e v e l o p m e n t of t h e c a r c i n o m a ? A s the patients with t u m o u r s d e t e c t e d early b y m a s s r a d i o g r a p h y d i d n o t have significantly lower serum I g E values t h a n t h e r e m a i n d e r of t h e p a t i e n t s w h o s e t u m o u r was d e t e c t e d later, the I g E elevation m u s t e i t h e r o c c u r early in t h e disease o r exist b e f o r e t h e carcinoma develops.
80
Thorstein Bl6ndal and Enn N~u
T h e elevation of serum IgE which is to be found in bronchial carcinoma has also been observed in other neoplasms, particularly those affecting T cells, when T cell dysfunction or fall in T cell levels has been assumed to give rise to high IgE concentrations (Waldman et al. 1974; Winters & Heiner 1976; Rosenbaum & Dwyer 1977). I m m u n e status in general (Krant et al. 1968; Brugarolas & Takita 1973) and T cell count in particular (Dellon et al. 1975) have been reported to be reduced in bronchial carcinoma. T h e r e are some results in this study that might support the concept of a link between T celts and serum IgE, one being the fact that the highest IgE values are seen in the most aggressive form of carcinoma (small cell carcinoma). Initially we believed that the high serum IgE levels reported by Waldmann et al. (1974) and Lfithgens et al. (1977) could be explained by the inclusion of atopic patients in their study. However, we have obtained the same results after exclusion of all patients with asthma, eczema and hay fever. This does not necessarily mean that bronchial carcinoma and elevated serum IgE levels are in any way connected. Some third factor might be as yet unidentified and would of c0urse be overlooked in our selection of the control group and the study population. REFERENCES
BRUGAROLAS,A. & TAKITA, H. (1973) Immunologic status in lung cancer. Chest 64, 427. DELLON, A. L., POTVIN, C. & CHRETIEN, P. B. (1975) Thymus-dependent lymphocyte levels in bronch0genic carcinoma; Correlations with histology, clinical stage and clinical course after surgical treatment. Cancer 35, 687. FEINSTEIN, A. R. (1968) A new staging system for cancer and reappraisal of 'early' treatment and 'cure' by radical surgery. New Engl. J. Med. 279, 74-7. JOHANSSON, S. G. O., BERGLUND,A. & KJELLMAN,N.-I.M. (1976) Comparison of IgE values as determined by different solid phase radioimmunoassay methods. Clin. Allergy 6, 91. KRANT, M. J., MANSKOPF,G., BaANDRUP, C. S. & MADOFF, M. A. (1968) Immunologic alterations in bronchogenic cancer. Cancer 21, 623. KREYBERG, L. (1967) Histological Typing of Lung Tumours. International Histological Classification of Tumours. Geneva: WHO. LI~THGENS,M., SCHLEGEL,G., HAUG, H., HELLRIEGEL,W., FILKE, F. & BIHLMAIER,K. (1977) Radioimmunologische Bestirnmung des Immunglobulins E bei Neoplasmen. Fortschr. Med. 95, 278. NOU, E., STENKVIST,B. & GRAEFMAN, S. (1979) Bronchial carcinoma I. A prospective five years study of an unselected carcinoma population in a Swedish county. Scand. ft. resp. Dis. 104, 43. PAUWELL,R. & STIRAETEN,M. (1975) Circulating IgE levels in patients with cancer. Lancet 1, 396. ROSENBAUNI,J. T. & DWYER, J. M. (1977) The role of IgE in the immune response to neoplasia: A review. Cancer 39, 11. SERROU, B. & DUBOIS, J. B. (1975) IgE serum-levels in cancer patients. Lancet 1, 582. WALDMANN, T. A., BULL, J. M., BRUCE, R. M., BRODER, S., JOST, M. C., BALESTRA, S. T. SuErs, M. E. (1974) Serum imrnunoglobulin E levels in patients with neoplastic disease. ft. Immunol. 113, 379. WINTERS, W. D. & HEINER, D. C. (1976) IgE levels in sera of cancer patients. J. Allergy din. Immunol. 57, 181.
C I R C U L A T I N G IgE LEVELS IN PATIENTS W I T H BRONCHIAL CARCINOMA THORSTEIN BLONDAL AND ENN N6U
Department of Lung Medicine, University of Uppsala, Sweden
SummaFy Serum I g E m e a s u r e m e n t s in 107 patients with bronchial carcinoma revealed statistically significant elevations w h e n c o m p a r e d to a control population. S e r u m I g E elevation was seen in 21.5% of the sample (23 of 107) and in all histological types at all clinical stages of the disease. It appears to occur early in the disease or possibly before the d e v e l o p m e n t of the carcinoma.
INTRODUCTION In recent years several reports have appeared on s e r u m levels of I g E in p r i m a r y bronchial carcinoma. Some authors have f o u n d raised levels of I g E ( W a l d m a n et al. 1974; Lfithgens et al. 1977) while others did not find any differences f r o m the levels in n o r m a l controls (Winters & H e i n e r 1976; Pauwell & Straeten 1975; Serrou & D u b o i s 1975). T o the best of our knowledge the following s t u d y of I g E in bronchial carcinoma is the first in which measurements have been carried out in an unselected population of patients.
Methods Serum samples were collected from 107 patients during a prospective epidemiological survey of primary bronchial carcinoma in the County of Uppsala in Sweden during the years 1974-6 (N~u et al. 1979). The clinicoanatomical stages (Feinstein 1968) of the disease were grouped as follows: A. Limited disease with local metastases (clinicoanatomical stages 1-3). B. Advanced disease with distant metastases (clinicoanatomical stage 4). The tumours were classified according to the W H O histopathological classification (Kreyberg 1967) as epidermoid carcinoma (WHO I), small cell anaplastic (WHO II), adenocarcinoma (WHO III) and large cell carcinoma (WHO IV). There were no tumours belonging to the group of combined epidermoid and adenocarcinoma (WHO V). The IgE determinations were performed at the Blood Centre of the University Hospital in Uppsala. The serum IgE concentrations were measured by the paper disc R I S T (PRIST) method (Johansson et al. 1976). For comparisons a population of 175 adults was used. These persons were selected from participants in a health survey in the county of Uppsala. Individuals with a history of asthma, allergic rhinitis, urticaria or atopic eczema were excluded. In this control material there were no significant changes in the IgE concentrations with respect to sex or age. 114 patients with carcinoma were detected in the survey. Seven patients suffering from the allergic diseases mentioned above were eliminated from the study, leaving a final total of 107 individuals.
78
Thorstein Bldndal and Enn NSu
As s e r u m IgE c o n c e n t r a t i o n s are n o t d i s t r i b u t e d in a n o r m a l m a n n e r the log10 of the i m m u n o globulin c o n c e n t r a t i o n was used in the statistical analyses w h i c h were p e r f e r m e d b y S t u d e n t ' s t-test and the X2 test.
RESULTS
Of the 107 patients with bronchial carcinoma, 84 were male. Fig. 1 shows serum IgE concentrations of patients with carcinoma; 24 of the values lie outside the 2 SD confidence limits of the control group, 23 above and one below. The increase in serum IgE levels with age is in contrast to the lack of significant trends
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omen
• Women
L. OO 0 c 030
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70
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.
•
y = O,O07X + 0,9718
o .
.
.
.
.
.
.
.
.
I
I
J
80
90
100
Age in years Fig. 1. Serum IgE levels in patients with carcinoma plotted against age. The difference in level between men and women is not significant (P<0.1). Note the male preponderance among the patients as a whole (78.5%) as well as amongst those with elevated serum IgE levels (87%). Dotted lines represent the 95 % confidence limits of results from the control group
with age in the control population. The geometric mean IgE concentrations are significantly elevated above normal in patients with carcinoma (Table I) and in each of the four histological groups (Table II). The difference is largest in the group with small cell carcinoma (43.5 ku/litre) and smallest in the adenocarcinoma group (16 kv/litre). Analysis of the results according to clinicoanatomical stage showed no statistically significant differences (Table III). Tumours detected by mass miniature radiography constitute 24 of 107 (22.4%). The geometric mean value of the serum IgE in these patients was 47.3 kv/litre compared to 43.3 ku/litre in the remainder of the patients. This difference is not statistically significant at the 95% confidence level.
I g E Levels in Bronchial Carcinoma
79
Table I. Serum IgE concentrations in 107 patients with bronchial carcinoma and in 175 controls
n Bronchial carcinoma Controls P
107 175
~ 44.2 14 < 0.001
+ 2 SD
Range
2.3-856.7 1.6-122
1-4700 0.1-133
Data presented as geometric mean with 95 % interval. Table II. Serum IgE concentrations in four histological groups of bronchial carcinoma compared to controls Histological group
n
,~
_ 2 SD
Epidermoid (I) Small cell (II) Adenocarcinoma (III) Large cell (IV)
51 21 31 4
48.0 57.5 30.0 75.0
1.9-1215.1 2.2-1510.9 3.0-295.7 12.8-438.1
Controls
175
14
1.6-122
The difference between the geometric mean values in each carcinoma group and that of the control group is statistically significant (P less than 0.001 for groups I, II and I I I and less than 0.01 for group IV). Table I l L Serum IgE levels in patients with limited disease (clinicoanatomical stages 1-3) compared to the serum IgE levels in patients with widespread disease (clinicoanatomical stage 4) Histological group
Epidermoid Small cell Adenocarcinoma Large cell
Clinicoanatomical stage
n
x
1-3 4 1-3 4 1-3 4 1-4
38 13 6 15 ' 22 9 4
50.5 41.4 26.3 78.6 36,5 18.6 75.0
The difference between the geometric mean values within each histological group (limited disease vs advanced) was not statistically significant in any group.
DISCUSSION Our study has c o n f i r m e d p r e v i o u s r e p o r t s of r a i s e d s e r u m IgE levels in b r o n c h i a l carcinoma. Does this e l e v a t i o n o c c u r b e f o r e or after d e v e l o p m e n t of t h e c a r c i n o m a ? A s the patients with t u m o u r s d e t e c t e d early b y m a s s r a d i o g r a p h y d i d n o t have significantly lower serum I g E values t h a n t h e r e m a i n d e r of t h e p a t i e n t s w h o s e t u m o u r was d e t e c t e d later, the I g E elevation m u s t e i t h e r o c c u r early in t h e disease o r exist b e f o r e t h e carcinoma develops.
80
Thorstein Bl6ndal and Enn N~u
T h e elevation of serum IgE which is to be found in bronchial carcinoma has also been observed in other neoplasms, particularly those affecting T cells, when T cell dysfunction or fall in T cell levels has been assumed to give rise to high IgE concentrations (Waldman et al. 1974; Winters & Heiner 1976; Rosenbaum & Dwyer 1977). I m m u n e status in general (Krant et al. 1968; Brugarolas & Takita 1973) and T cell count in particular (Dellon et al. 1975) have been reported to be reduced in bronchial carcinoma. T h e r e are some results in this study that might support the concept of a link between T celts and serum IgE, one being the fact that the highest IgE values are seen in the most aggressive form of carcinoma (small cell carcinoma). Initially we believed that the high serum IgE levels reported by Waldmann et al. (1974) and Lfithgens et al. (1977) could be explained by the inclusion of atopic patients in their study. However, we have obtained the same results after exclusion of all patients with asthma, eczema and hay fever. This does not necessarily mean that bronchial carcinoma and elevated serum IgE levels are in any way connected. Some third factor might be as yet unidentified and would of c0urse be overlooked in our selection of the control group and the study population. REFERENCES
BRUGAROLAS,A. & TAKITA, H. (1973) Immunologic status in lung cancer. Chest 64, 427. DELLON, A. L., POTVIN, C. & CHRETIEN, P. B. (1975) Thymus-dependent lymphocyte levels in bronch0genic carcinoma; Correlations with histology, clinical stage and clinical course after surgical treatment. Cancer 35, 687. FEINSTEIN, A. R. (1968) A new staging system for cancer and reappraisal of 'early' treatment and 'cure' by radical surgery. New Engl. J. Med. 279, 74-7. JOHANSSON, S. G. O., BERGLUND,A. & KJELLMAN,N.-I.M. (1976) Comparison of IgE values as determined by different solid phase radioimmunoassay methods. Clin. Allergy 6, 91. KRANT, M. J., MANSKOPF,G., BaANDRUP, C. S. & MADOFF, M. A. (1968) Immunologic alterations in bronchogenic cancer. Cancer 21, 623. KREYBERG, L. (1967) Histological Typing of Lung Tumours. International Histological Classification of Tumours. Geneva: WHO. LI~THGENS,M., SCHLEGEL,G., HAUG, H., HELLRIEGEL,W., FILKE, F. & BIHLMAIER,K. (1977) Radioimmunologische Bestirnmung des Immunglobulins E bei Neoplasmen. Fortschr. Med. 95, 278. NOU, E., STENKVIST,B. & GRAEFMAN, S. (1979) Bronchial carcinoma I. A prospective five years study of an unselected carcinoma population in a Swedish county. Scand. ft. resp. Dis. 104, 43. PAUWELL,R. & STIRAETEN,M. (1975) Circulating IgE levels in patients with cancer. Lancet 1, 396. ROSENBAUNI,J. T. & DWYER, J. M. (1977) The role of IgE in the immune response to neoplasia: A review. Cancer 39, 11. SERROU, B. & DUBOIS, J. B. (1975) IgE serum-levels in cancer patients. Lancet 1, 582. WALDMANN, T. A., BULL, J. M., BRUCE, R. M., BRODER, S., JOST, M. C., BALESTRA, S. T. SuErs, M. E. (1974) Serum imrnunoglobulin E levels in patients with neoplastic disease. ft. Immunol. 113, 379. WINTERS, W. D. & HEINER, D. C. (1976) IgE levels in sera of cancer patients. J. Allergy din. Immunol. 57, 181.