Archives of Disease in Childhood, 1978, 53, 366-374
Clinical applications of serum carcinoembryonic antigen and alpha-fetoprotein levels in children with solid tumours J. R. MANN, G. E. LAKIN, J. C. LEONARD, H. A. RAWLINSON, S. G. N. RICHARDSON, J. J. CORKERY, A. H. CAMERON, AND K. J. SHAH From Birmingham Children's Hospital; Department of Experimental Pathology, University of Birmingham; and Department of Medical Genetics, Royal Hospital for Sick Children, Glasgow SUMMARY A study was carried out on serum carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP) levels, both measured by radioimmunoassay, in 88 children with malignant solid tumours and in 26 children with nonmalignant disorders, who presented during the years 1973-77. Slightly or moderately raised CEA levels were found at presentation in 11 of 66 children with malignant tumours, in 2 others with recurrent tumours, and in 4 children with nonmalignant disorders. Raised CEA levels generally indicated advanced malignant disease, often affecting the liver, or other hepatic disorders, but were not associated with a specific tumour type. Except in the first months of life, significantly raised AFP levels were detected only in 11 patients with yolk sac-derived tumours, or hepatomas, and in one child with tyrosinosis who later developed a malignant hepatoma. Serial measurements of AFP accurately reflected the clinical response to treatment and in 2 patients indicated recurrence before this could be detected clinically.
Carcinoembryonic antigen (CEA), a glycoprotein, was first found as an apparently specific surface antigen associated with adenocarcinoma of the human colon by Gold and Freedman (1965). However, although about 70% of patients with gastrointestinal malignancy have raised levels, raised CEA has since been found in patients with other adult cancers (Booth et al., 1973; Neville and Laurence, 1974) and certain nonmalignant disorders. Nevertheless, serial studies have shown that in adult patients with CEA-releasing colorectal carcinomas serum levels fall if treatment is successful and rise again when metastases occur (Booth et al., 1974). Studies of serum CEA in children with neuroblastoma (Reynoso et al., 1972; Wang et al., 1974; Frens et al., 1976) showed that serum CEA levels were usually raised when active tumour was present and fell when treatment was successful. That CEA may act as a tumour marker in paediatric malignancy was also suggested by Felberg et al. (1976), who found raised levels in retinoblastoma patients. Alpha-fetoprotein (AFP), a fetal protein chemically similar to albumin, was first identified by Received 7 October 1977
366
Pedersen in 1944. Raised serum levels were described in association with hepatomas in rodents (Abelev et al., 1963) and humans (Tatarinov, 1964) and in patients with malignant gonadal teratoblastomas (Abelev et al., 1967). Raised levels have also been found in patients with certain nonmalignant disorders (Neville and Cooper, 1976). Early studies (Abelev et al., 1967; Masopust et al., 1968; Mawas et al., 1969) of over 300 children with malignant tumours, using comparatively insensitive bidimensional immunodiffusion methods, showed detectably raised levels in a proportion of children with teratomata, gonadal embryonal carcinomata, hepatoblastoma, and hepatocellular carcinoma, but in none with the commoner tumours such as neuroblastoma and nephroblastoma. Radioimmunoassay has increased the sensitivity of the test by more than 1000-fold, and has permitted the detection of AFP in sera from most children with yolk sac-derived and hepatic malignancies. Studies in some 30 paediatric cancer patients suggest that AFP monitoring by this sensitive method may be of value during treatment (Hagesawa et al., 1972, 1973; Takahashi, 1973; Itoh et al., 1974; Kohn and Weaver, 1974; Teilum et al., 1974; Pick et al., 1975; N0rgaard-Pedersen et al., 1975,
Clinical applications of serum carcinoembryonic antigen 367 1976; Tsuchida et al., 1975; Palmer et al., 1976; Urano et al., 1976; Shirai et al., 1976; Sakashita et al., 1976; Schoenfeld et al., 1976; Grigor et al., 1977). The purpose of our study was to define the frequency of raised serum CEA and AFP levels, both measured by radioimmunoassay, in children with malignant solid tumours, and to assess the clinical value of serial measurements in monitoring response to therapy and detecting tumour recurrence. We also report the findings in 25 children with nonmalignant disorders. Patients and methods
Eighty-eight children referred during 1973-77 for treatment of malignant solid tumours and 26 children being investigated or treated for what proved to be nonmalignant conditions were studied. In patients found to have raised CEA or AFP levels serial venepunctures were performed to assess the relationship between the serum levels and response to therapy. In other patients blood for CEA and AFP levels was taken during venepuncture for other investigations, or for the administration of cytotoxic drugs. The patients' ages ranged from 5 days to 15 years, 11 being aged less than one year, and their diagnoses are shown in Tables 1 and 2. CEA levels were measured by the double-antibody technique, the 95% confidence limits of normal healthy adults being 0-15 ng/ml, standard error 1 9 (Booth et al., 1974). In some patients a comparison was made, using the same sera, with CEA levels measured by the Z-gel method (Lo Gerfo et al., 1971), the normal upper limit in healthy adults being 2 5 ng/ml, the reproducibility of the CEA Roche 0 5 ng/ml at this level. assay being AFP levels, normally less than 25 ng/ml in adults (Grigor et al., 1977), were measured by radioimmunoassay. In the first 18 patients AFP Table
1
Details ofpatients with malignant tumours No.
Lymphoma (lymphosarcoma 7, histiocytic lymphoma 2, Hodgkin's disease 4) Wilms's tumour Mesenchymal tumours (rhabdomyosarcoma 10, undifferentiated sarcoma 3, leiomyosarcoma 1, fibrosarcoma 1)
13 26 15
Neuroblastoma Yolk sac-derived tumours (ovarian embryonal carcinoma 1, orchioblastoma 4, sacrococcygeal teratoma I' Hepatomas Other tumours (Ewing's sarcoma 2, medulloblastoma 1, pulmonary blastoma 1, optic glioma 1, ependymoma 1, branchial cleft carcinoma 1, glomus tumour 1, uncertain 3)
12
Total
88
6
of patients
estimations were done in the Department of Cancer Studies, University of Birmingham; in this laboratory the levels in healthy adult males and nonpregnant females were in the range 1-19 ng/ml (mean ± SD 9 3 + 8-6). Sera from subsequent patients were tested in the Department of Medical Genetics, Glasgow, using the method of Vince et al. (1975), the lower limit of sensitivity varying from
Clinical applications of serum carcinoembryonic antigen and alpha-fetoprotein levels in children with solid tumours J. R. MANN, G. E. LAKIN, J. C. LEONARD, H. A. RAWLINSON, S. G. N. RICHARDSON, J. J. CORKERY, A. H. CAMERON, AND K. J. SHAH From Birmingham Children's Hospital; Department of Experimental Pathology, University of Birmingham; and Department of Medical Genetics, Royal Hospital for Sick Children, Glasgow SUMMARY A study was carried out on serum carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP) levels, both measured by radioimmunoassay, in 88 children with malignant solid tumours and in 26 children with nonmalignant disorders, who presented during the years 1973-77. Slightly or moderately raised CEA levels were found at presentation in 11 of 66 children with malignant tumours, in 2 others with recurrent tumours, and in 4 children with nonmalignant disorders. Raised CEA levels generally indicated advanced malignant disease, often affecting the liver, or other hepatic disorders, but were not associated with a specific tumour type. Except in the first months of life, significantly raised AFP levels were detected only in 11 patients with yolk sac-derived tumours, or hepatomas, and in one child with tyrosinosis who later developed a malignant hepatoma. Serial measurements of AFP accurately reflected the clinical response to treatment and in 2 patients indicated recurrence before this could be detected clinically.
Carcinoembryonic antigen (CEA), a glycoprotein, was first found as an apparently specific surface antigen associated with adenocarcinoma of the human colon by Gold and Freedman (1965). However, although about 70% of patients with gastrointestinal malignancy have raised levels, raised CEA has since been found in patients with other adult cancers (Booth et al., 1973; Neville and Laurence, 1974) and certain nonmalignant disorders. Nevertheless, serial studies have shown that in adult patients with CEA-releasing colorectal carcinomas serum levels fall if treatment is successful and rise again when metastases occur (Booth et al., 1974). Studies of serum CEA in children with neuroblastoma (Reynoso et al., 1972; Wang et al., 1974; Frens et al., 1976) showed that serum CEA levels were usually raised when active tumour was present and fell when treatment was successful. That CEA may act as a tumour marker in paediatric malignancy was also suggested by Felberg et al. (1976), who found raised levels in retinoblastoma patients. Alpha-fetoprotein (AFP), a fetal protein chemically similar to albumin, was first identified by Received 7 October 1977
366
Pedersen in 1944. Raised serum levels were described in association with hepatomas in rodents (Abelev et al., 1963) and humans (Tatarinov, 1964) and in patients with malignant gonadal teratoblastomas (Abelev et al., 1967). Raised levels have also been found in patients with certain nonmalignant disorders (Neville and Cooper, 1976). Early studies (Abelev et al., 1967; Masopust et al., 1968; Mawas et al., 1969) of over 300 children with malignant tumours, using comparatively insensitive bidimensional immunodiffusion methods, showed detectably raised levels in a proportion of children with teratomata, gonadal embryonal carcinomata, hepatoblastoma, and hepatocellular carcinoma, but in none with the commoner tumours such as neuroblastoma and nephroblastoma. Radioimmunoassay has increased the sensitivity of the test by more than 1000-fold, and has permitted the detection of AFP in sera from most children with yolk sac-derived and hepatic malignancies. Studies in some 30 paediatric cancer patients suggest that AFP monitoring by this sensitive method may be of value during treatment (Hagesawa et al., 1972, 1973; Takahashi, 1973; Itoh et al., 1974; Kohn and Weaver, 1974; Teilum et al., 1974; Pick et al., 1975; N0rgaard-Pedersen et al., 1975,
Clinical applications of serum carcinoembryonic antigen 367 1976; Tsuchida et al., 1975; Palmer et al., 1976; Urano et al., 1976; Shirai et al., 1976; Sakashita et al., 1976; Schoenfeld et al., 1976; Grigor et al., 1977). The purpose of our study was to define the frequency of raised serum CEA and AFP levels, both measured by radioimmunoassay, in children with malignant solid tumours, and to assess the clinical value of serial measurements in monitoring response to therapy and detecting tumour recurrence. We also report the findings in 25 children with nonmalignant disorders. Patients and methods
Eighty-eight children referred during 1973-77 for treatment of malignant solid tumours and 26 children being investigated or treated for what proved to be nonmalignant conditions were studied. In patients found to have raised CEA or AFP levels serial venepunctures were performed to assess the relationship between the serum levels and response to therapy. In other patients blood for CEA and AFP levels was taken during venepuncture for other investigations, or for the administration of cytotoxic drugs. The patients' ages ranged from 5 days to 15 years, 11 being aged less than one year, and their diagnoses are shown in Tables 1 and 2. CEA levels were measured by the double-antibody technique, the 95% confidence limits of normal healthy adults being 0-15 ng/ml, standard error 1 9 (Booth et al., 1974). In some patients a comparison was made, using the same sera, with CEA levels measured by the Z-gel method (Lo Gerfo et al., 1971), the normal upper limit in healthy adults being 2 5 ng/ml, the reproducibility of the CEA Roche 0 5 ng/ml at this level. assay being AFP levels, normally less than 25 ng/ml in adults (Grigor et al., 1977), were measured by radioimmunoassay. In the first 18 patients AFP Table
1
Details ofpatients with malignant tumours No.
Lymphoma (lymphosarcoma 7, histiocytic lymphoma 2, Hodgkin's disease 4) Wilms's tumour Mesenchymal tumours (rhabdomyosarcoma 10, undifferentiated sarcoma 3, leiomyosarcoma 1, fibrosarcoma 1)
13 26 15
Neuroblastoma Yolk sac-derived tumours (ovarian embryonal carcinoma 1, orchioblastoma 4, sacrococcygeal teratoma I' Hepatomas Other tumours (Ewing's sarcoma 2, medulloblastoma 1, pulmonary blastoma 1, optic glioma 1, ependymoma 1, branchial cleft carcinoma 1, glomus tumour 1, uncertain 3)
12
Total
88
6
of patients
estimations were done in the Department of Cancer Studies, University of Birmingham; in this laboratory the levels in healthy adult males and nonpregnant females were in the range 1-19 ng/ml (mean ± SD 9 3 + 8-6). Sera from subsequent patients were tested in the Department of Medical Genetics, Glasgow, using the method of Vince et al. (1975), the lower limit of sensitivity varying from
