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Half-life of alpha-fetoprotein in neonatal sacrococcygeal teratoma
YJPSU-58779; No of Pages 5 Journal of Pediatric Surgery xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Half-life of alpha-fetoprotein in neonatal sacrococcygeal teratoma So Hyun Nam a, Min Jeng Cho b, Dae Yeon Kim c, Seong Chul Kim c,⁎ a b c
Department of Surgery, Dong-A University College of Medicine, Dong-A University Hospital Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea Department of Pediatric Surgery, University of Ulsan College of Medicine, Asan Medical Center
a r t i c l e
i n f o
Article history: Received 9 August 2018 Accepted 25 August 2018 Available online xxxx Key words: Sacrococcygeal teratoma Alpha-fetoprotein Tumor marker
a b s t r a c t Background: Alpha-fetoprotein (AFP) is useful as a tumor marker for sacrococcygeal teratoma (SCT). We investigated the half-life of AFP in SCT. Methods: Neonates who underwent surgical treatment for SCT between 1997 and 2016 were included in the study, whereas patients who died before or after surgery or had malignant germ cell tumors were excluded. Results: Fifty-five non-recurrent SCT patients (M:F = 18:37) were enrolled. They underwent surgery on average 7.4 ± 4.1 days after birth. Serum AFP was measured an average 4.25 ± 2.07 times per patient. We obtained 165 half-lives following the formula (M = Mo * (1/2) Δt/T). A positive correlation was observed between half-life and patient age using the formula T1/2 = 0.0597 × days +6.1643 (p b 0.001). It was different from recurrent SCT (T1/2 = 0.1196 × days −0.0633) (p b 0.05). Half-life was different between mature SCT (T1/2 = 0.0671 × days +4.3912) and immature SCT (T1/2 = 0.0433 × days +8.9339) (p b 0.05). Conclusion: The half-life of AFP in neonatal patients with SCT was prolonged in proportion to the age, and it was getting longer in recurrent tumor than non-recurrent tumor. The half-life of AFP was longer in immature teratoma than in mature teratoma. Level of Evidence: IV. © 2018 Elsevier Inc. All rights reserved.
Sacrococcygeal teratoma (SCT) is the most common neonatal tumor, and is particularly predominant in females [1–3]. Its incidence ranges from 1 in every 35,000–40,000 births; a higher incidence has been reported in a recent European study (range, between 1/10,700 and 1/ 14,000 births) [2]. Overall prognosis is favorable; however, prognosis is relatively unfavorable for patients prenatally diagnosed with SCT. Factors related to high mortality include large tumor size, high ratio of tumor volume to fetal weight, vascularization, solid morphology, presence of polyhydramnios, cardiac decompression, and large placenta size [1,2]. The treatment of choice is complete surgical excision of SCT and removal of coccyx. A 4%–21% recurrence rate has been reported, with half occurring as malignant yolk sac tumors [3]. For follow-up after surgery, image study using ultrasonography or MRI, and serum tumor markers are useful. Serum alpha-fetoprotein (AFP) has been useful tumor markers for SCT, malignant germ cell tumors, and hepatic tumors in children [3,4]. Increased serum AFP levels and prolonged halflife are predictors of recurrence [5]. However, as the serum AFP was originally high in the normal fetus and infants, it is difficult to interpret the serum AFP figures when predicting recurrence of SCT [6–10]. In 1981, Wu et al. found that the rate of decline was most rapid between ⁎ Corresponding author at: (138-736) Asan Medical Center, 388-1, Poognap-dong, Songpa-gu, Seoul, Korea. Tel.: +82 2 3010 3498; fax: +82 2 3010 6863. E-mail address: [email protected] (S.C. Kim).
birth and 2 weeks of age with 5.5 days of half-life of AFP, and serum AFP level had reached at adult level after 8 months of age [7]. The measured half-life of AFP in normal infants was not rectilinear [8]. The difference in serum AFP levels between normal infants and patients who underwent surgery for SCT was not evaluated yet. In the current study, we investigated the half-life of AFP in SCT based on pathology and compared it with that of normal infants, available in the literature. We also aimed to confirm the value of AFP half-life as a predictor of SCT recurrence. 1. Materials and methods 1.1. Inclusion criteria Patients who were treated for SCT between 1997 and 2016 at the Asan Medical Center, Seoul, Korea were retrospectively reviewed. Neonates who underwent surgical treatment for SCT and had their serum AFP evaluated after surgery were included in the study. We excluded the patients who died before/after surgery, had malignant germ cell tumor, or had serum AFP check less than three times. The patients who had hepatic dysfunction or renal disease were excluded. During the study period, 70 patients with SCT were admitted to the neonatal intensive care unit. Five patients were excluded; one baby died before surgery, two patients died after surgery. One was confirmed as having yolk
https://doi.org/10.1016/j.jpedsurg.2018.08.012 0022-3468/© 2018 Elsevier Inc. All rights reserved.
Please cite this article as: Nam SH, et al, Half-life of alpha-fetoprotein in neonatal sacrococcygeal teratoma, J Pediatr Surg (2018), https://doi.org/ 10.1016/j.jpedsurg.2018.08.012
2
S.H. Nam et al. / Journal of Pediatric Surgery xxx (xxxx) xxx–xxx
Fig. 1. Study population ⁎: sacrococcygeal teratoma +: alpha-fetoprotein.
sac tumor, and one did not have N2 AFP values. Of the 65 patients, 10 exhibited recurrence, with 4 (40%) having yolk sac tumor (Fig. 1).
1.2. Data collection Medical records were retrospectively reviewed for gestational age, gender, birth weight, Apgar score, mother's age, delivery method, prenatal treatment, associated anomalies, age and body weight at surgery, operating time, and operative approach. To describe tumor biology, we collected the data for Altman classification, maximal diameter in preoperative imaging study, tumor diameter and weight after excision, and pathologic diagnosis.
1.3. Measurement of AFP and calculation of half-life Serum AFP was obtained from all patients prior to surgery. A protocol for AFP follow-up testing was lacking; however, AFP was measured every 1–3 months at outpatient clinics. The date of examination and the serum AFP values for the age of 2 years were collected. AFP was measured by a chemiluminescent microparticle immunoassay (CMIA) using an Abbott Architect Analyzer (Abbott Laboratories, Abbott Park, IL, USA). The half-life was calculated by the formula M = Mo × (1/ 2) Δt/T, where Mo is the baseline AFP concentration before surgery, M is the measured serum AFP after Δt days and T is the half-life. T is calculated using the formula T = Δt/Log 2 (Mo/M).
Fig. 2. Serum AFP levels between non-recurrent SCT and recurrent SCT ⁎: alpha-fetoprotein +: sacrococcygeal teratoma.
Please cite this article as: Nam SH, et al, Half-life of alpha-fetoprotein in neonatal sacrococcygeal teratoma, J Pediatr Surg (2018), https://doi.org/ 10.1016/j.jpedsurg.2018.08.012
S.H. Nam et al. / Journal of Pediatric Surgery xxx (xxxx) xxx–xxx
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Fig. 3. Half-life of AFP with reference to preoperative AFP in non-recurrent SCT ⁎: alpha-fetoprotein.
4.3 cm (range, 1.5–19 cm) as revealed by specimens. Forty one tumors were mature teratoma and 14 were immature teratoma.
1.4. Statistical analysis Linear regression analysis was conducted using the IBM SPSS Statistics software (version 20 for Windows; SPSS Inc., Chicago, IL), and the Chow test was used to compare linear regressions. P b 0.05 was considered statistically significant. The Sigma XL software (version 8, SigmaXL Inc., Kitchener, ON, Canada) was used to graph data with 95% confidence intervals (CI) and predictive intervals (PI). 2. Results 2.1. Clinical data Fifty-five non-recurrent SCT patients (M:F = 18:37) were enrolled. Mean gestational age was 37.5 ± 2.9 weeks and birth weight was 3,193.3 ± 641.1 g. Four babies underwent fetal intervention with radiofrequency ablation (RFA).They underwent surgery on average 7.4 ± 4.1 days after birth, and mean operating time was 150.5 ± 87.1 min. Standard posterior approach was possible in 52 patients, whereas 3 needed additional laparotomy. Altman tumor classification was as follows: type I lesions, 16 (29.1%); type II, 19 (34.5%); type III, 16 (29.1%); and type IV, 4 (7.3%). The tumor size was 7.4 ± 4.2 cm (range, 1.6–17 cm) as revealed by imaging, whereas it was 6.9 ±
2.2. Measurement and half-life of AFP Serum AFP was measured approximately 4.25 ± 2.07 times per patient within 2 years of age. The serum AFP of non-recurrent and recurrent tumors is indicated in Fig. 2; 165 half-lives were calculated. A significant correlation was observed between half-life and patient age using the formula (T1/2 = 0.0597 × days + 6.1643, R 2 = 0.4888, Durbin–Watson = 1.908, p b 0.001) (Fig. 3). A significant difference was observed between mature and immature SCT (p b 0.05). For mature SCT, half-life was calculated using the formula T1/2 = 0.0671 × days +4.3912, R 2 = 0.9042, Durbin–Watson = 2.064, p b 0.001), whereas for immature SCT, half-life was calculated using the formula T1/2 = 0.0433 × days + 8.9339, R 2 = 0.1336, Durbin–Watson = 2.222, p = 0.003 (Figs. 4 & 5). To compare the AFP half-life of the recurred tumor, we collected the serum AFP before the recurrence was confirmed. For recurrent SCT, halflife was calculated using the formula T1/2 = 0.1196 × days − 0.0633, R 2 = 0.3617, Durbin–Watson = 0.827, p b 0.001 (Fig. 6). A significant difference was shown between recurrent and non-recurrent SCT (p b 0.05).
Fig. 4. Half-life of AFP with reference to preoperative AFP in mature SCT ⁎: alpha-fetoprotein.
Please cite this article as: Nam SH, et al, Half-life of alpha-fetoprotein in neonatal sacrococcygeal teratoma, J Pediatr Surg (2018), https://doi.org/ 10.1016/j.jpedsurg.2018.08.012
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S.H. Nam et al. / Journal of Pediatric Surgery xxx (xxxx) xxx–xxx
Fig. 5. Half-life of AFP with reference to preoperative AFP in immature SCT ⁎: alpha-fetoprotein.
3. Discussion AFP is a single chain glycoprotein; it is normally produced by the fetal yolk sac, liver, and gastrointestinal tract [10]. Serum AFP is elevated in cases of hepatic disorders, including acute hepatitis, liver cirrhosis, liver abscess, some hereditary disorders including ataxia telangiectasia and hereditary tyrosinemia type 1, and tumors, such as hepatocellular carcinoma, hepatoblastoma, germ cell tumors, pancreaticoblastoma, and retinoblastoma [6]. Secretion of AFP is also important for detecting malignant germ cell tumors with yolk sac tumor differentiation [3–6]. In cases of immature teratomas, AFP is elevated despite histologic examination being unable to detect the yolk sac tumor component [6]. AFP measurement is essential to evaluate the efficacy of germ cell tumor treatments and to predict tumor recurrence. During fetal period, AFP is primarily produced by the fetal yolk sac and liver [6,9]. After yolk sac degeneration, the fetal liver is the main site of AFP synthesis; thus, serum AFP is generally highly elevated in neonates (full-term neonates, 41,687 μg/L; preterm neonates, 158,125 μg/L) [9]. Serum AFP is gradually decline postnatally and it begins to disappear from blood 2 weeks after birth [6,7]. The time to reaching normal adult levels is unclear though it was reported between 8 months and 2 years old; therefore, we need to pay attention to
interpret serum AFP in infants. Even if high serum AFP levels are detected in infants, it is not always associated with hepatitis, malignant tumors or recurrence. It should be based on reliable reference of AFP in infants. The previous AFP reference in normal infants based on age was limited; it also showed a broad range of values in literature. Wu et al. reported that the AFP degradation half-life was 5.5 days between birth and 2 weeks after birth, 11 days between 2 weeks to 2 months after birth, and 33 days between 2 and 4 months of age after birth [7]. Blohm et al. reported different half-life ranges between term and premature babies. The half-life was longer in premature babies in the early period (5.1 vs. 6 days in first week) [9]. Ohama et al. calculated the half-life of AFP at every 10 days of age in normal infants. They observed that the half-life was 3 days at 10 days after birth, 21 days at 60 days after, and 42 days at 120 days after birth [8]. Using 524 blood samples of 390 normal infants, Blohm et al. observed that the AFP levels had not reached the adult serum AFP levels by the age of 2 years [9]. All three reports showed different references. Additionally, they had not obtained AFP serially in a single patient; however, they had collected the values in individuals. In the present study, we showed a linear relationship between postnatal age and serum AFP half-life using blood samples serially in a single
Fig. 6. The half-life of AFP with reference to preoperative AFP in recurrent SCT ⁎: alpha-fetoprotein.
Please cite this article as: Nam SH, et al, Half-life of alpha-fetoprotein in neonatal sacrococcygeal teratoma, J Pediatr Surg (2018), https://doi.org/ 10.1016/j.jpedsurg.2018.08.012
S.H. Nam et al. / Journal of Pediatric Surgery xxx (xxxx) xxx–xxx
patient after SCT surgery. Based on the formula for non-recurrent SCT in the present study (T1/2 = 0.0597 × days + 6.1643), the half-life in 2 weeks after surgery is 7 days; this value is higher than the range in normal infants in previous reports [7–9]. However, in our results, the half-life value obtained was 9.74 days in 60 days after surgery and 13.32 days in 120 days. This suggests that the half-life of SCT is quite different from that of the reference value in normal infants in previous studies. Kohn proposed that the clearance rate of a serum tumor marker after treatment could have prognostic significance [11], indicating that the tumor marker would be decreased after resection, and that the rate of decrease would be faster after tumor resection. A prolonged half-life may indicate the remaining or recurrent tumor, which continues to produce AFP even though it cannot be revealed in image study [4,12]. Thus, we compared the half-life of AFP between non-recurrent and recurrent SCT. SCT can potentially undergo malignant transformation. It can probably be detected early by regularly screening AFP and using imaging studies [10]. Here, we found that half-life of AFP in recurrent SCT exhibited a different formula; the half-life was shorter than that of nonrecurrent tumor in early postoperative period, but gradually it was getting longer over time until a recurrence was found. We're certain that a sudden increase in AFP might probably indicate recurrence; however, during the follow-up period, slow degradation of AFP could also predict recurrence. In such a case, plans for short-term follow-up can be made based on the obtained results. This study also has several limitations. First, it was a retrospective study, and the measurement interval was inconsistent. Second, we did not compare the half-life of AFP between SCT patients and normal infants, because the measurement of AFP was not included in routine check-up for neonatal intensive care. Third, we calculated the half-life based on the preoperative serum AFP as it was T0. Scheduled sampling requires a prospectively designed protocol. Also half-life Tn~n + 1 should be obtained from time tn to tn + 1. We included the levels of serum AFP within 2 years of age, because as reported in literature, the serum AFP did not decrease until 2 years after birth. Further, the recurrence observed in the current study occurred within two years after the operation. We did not find the reason for different half-life between mature teratoma and immature teratoma, and also we didn't compare the tumor characteristics between recurrent SCT and non-recurrent SCT. It requires further study. Despite these limitations, we could show the change of AFP half-life in patients with SCT, and could relate it to the
5
tumor pathology and its recurrence. We hope that the results of the current study would serve as a meaningful guideline for AFP follow-up in SCT patients within 2 years of age. 4. Conclusion The half-life of AFP in neonatal patients with SCT was prolonged in proportion to the age, and it was getting longer in recurrent tumor than non-recurrent tumor. The half-life of AFP was longer in immature teratoma than in mature teratoma. Acknowledgment This work was supported by the Dong-A University research fund. References [1] Akinkuotu AC, Coleman A, Shue E, et al. Predictors of poor prognosis in prenatally diagnosed sacrococcygeal teratoma: a multiinstitutional review. J Pediatr Surg 2015;50:771–4. [2] Hambraeus M, Arnbjörnsson E, Börjesson A, et al. Sacrococcygeal teratoma: a population-based study of incidence and prenatal prognostic factors. J Pediatr Surg 2016;51:481–5. [3] Pauniaho SL, Tatti O, Lahdenne P, et al. Tumor markers AFP, CA 125, and CA 19-9 in the long-term follow-up of sacrococcygeal teratomas in infancy and childhood. Tumour Biol 2010;31:261–5. [4] Han SJ, Yoo S, Choi SH, et al. Actual half-life of alpha-fetoprotein as a prognostic tool in pediatric malignant tumors. Pediatr Surg Int 1997;12:599–602. [5] Keskin S, Ekenel M, Başaran M, et al. Predictive value of marker half-life in relapsed and nonrelapsed nonseminomatous germ cell testicular tumor patients undergoing chemotherapy. Am J Clin Oncol 2012;35:369–72. [6] Schneider DT, Calaminus G, Göbel U. Diagnostic value of alpha 1-fetoprotein and beta-human chorionic gonadotropin in infancy and childhood. Pediatr Hematol Oncol 2001;18:11–26. [7] Wu JT, Book L, Sudar K. Serum alpha fetoprotein (AFP) levels in normal infants. Pediatr Res 1981;15:50–2. [8] Ohama K, Nagase H, Ogino K, et al. Alpha-fetoprotein (AFP) levels in normal children. Eur J Pediatr Surg 1997;7:267–9. [9] Blohm ME, Vesterling-Hörner D, Calaminus G, et al. Alpha 1-fetoprotein (AFP) reference values in infants up to 2 years of age. Pediatr Hematol Oncol 1998;15:135–42. [10] Lahdenne P, Kuusela P, Siimes MA, et al. Biphasic reduction and concanavalin a binding properties of serum alpha-fetoprotein in preterm and term infants. J Pediatr 1991;118:272–6. [11] Kohn J. The dynamics of serum alpha-protein in the course of testicular teratoma. Scand J Immunol 8:103–7. [12] Shim JH, Han S, Lee YJ, et al. Half-life of serum alpha-fetoprotein: an early prognostic index of recurrence and survival after hepatic resection for hepatocellular carcinoma. Ann Surg 2013;257:708–17.
Please cite this article as: Nam SH, et al, Half-life of alpha-fetoprotein in neonatal sacrococcygeal teratoma, J Pediatr Surg (2018), https://doi.org/ 10.1016/j.jpedsurg.2018.08.012
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Half-life of alpha-fetoprotein in neonatal sacrococcygeal teratoma So Hyun Nam a, Min Jeng Cho b, Dae Yeon Kim c, Seong Chul Kim c,⁎ a b c
Department of Surgery, Dong-A University College of Medicine, Dong-A University Hospital Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea Department of Pediatric Surgery, University of Ulsan College of Medicine, Asan Medical Center
a r t i c l e
i n f o
Article history: Received 9 August 2018 Accepted 25 August 2018 Available online xxxx Key words: Sacrococcygeal teratoma Alpha-fetoprotein Tumor marker
a b s t r a c t Background: Alpha-fetoprotein (AFP) is useful as a tumor marker for sacrococcygeal teratoma (SCT). We investigated the half-life of AFP in SCT. Methods: Neonates who underwent surgical treatment for SCT between 1997 and 2016 were included in the study, whereas patients who died before or after surgery or had malignant germ cell tumors were excluded. Results: Fifty-five non-recurrent SCT patients (M:F = 18:37) were enrolled. They underwent surgery on average 7.4 ± 4.1 days after birth. Serum AFP was measured an average 4.25 ± 2.07 times per patient. We obtained 165 half-lives following the formula (M = Mo * (1/2) Δt/T). A positive correlation was observed between half-life and patient age using the formula T1/2 = 0.0597 × days +6.1643 (p b 0.001). It was different from recurrent SCT (T1/2 = 0.1196 × days −0.0633) (p b 0.05). Half-life was different between mature SCT (T1/2 = 0.0671 × days +4.3912) and immature SCT (T1/2 = 0.0433 × days +8.9339) (p b 0.05). Conclusion: The half-life of AFP in neonatal patients with SCT was prolonged in proportion to the age, and it was getting longer in recurrent tumor than non-recurrent tumor. The half-life of AFP was longer in immature teratoma than in mature teratoma. Level of Evidence: IV. © 2018 Elsevier Inc. All rights reserved.
Sacrococcygeal teratoma (SCT) is the most common neonatal tumor, and is particularly predominant in females [1–3]. Its incidence ranges from 1 in every 35,000–40,000 births; a higher incidence has been reported in a recent European study (range, between 1/10,700 and 1/ 14,000 births) [2]. Overall prognosis is favorable; however, prognosis is relatively unfavorable for patients prenatally diagnosed with SCT. Factors related to high mortality include large tumor size, high ratio of tumor volume to fetal weight, vascularization, solid morphology, presence of polyhydramnios, cardiac decompression, and large placenta size [1,2]. The treatment of choice is complete surgical excision of SCT and removal of coccyx. A 4%–21% recurrence rate has been reported, with half occurring as malignant yolk sac tumors [3]. For follow-up after surgery, image study using ultrasonography or MRI, and serum tumor markers are useful. Serum alpha-fetoprotein (AFP) has been useful tumor markers for SCT, malignant germ cell tumors, and hepatic tumors in children [3,4]. Increased serum AFP levels and prolonged halflife are predictors of recurrence [5]. However, as the serum AFP was originally high in the normal fetus and infants, it is difficult to interpret the serum AFP figures when predicting recurrence of SCT [6–10]. In 1981, Wu et al. found that the rate of decline was most rapid between ⁎ Corresponding author at: (138-736) Asan Medical Center, 388-1, Poognap-dong, Songpa-gu, Seoul, Korea. Tel.: +82 2 3010 3498; fax: +82 2 3010 6863. E-mail address: [email protected] (S.C. Kim).
birth and 2 weeks of age with 5.5 days of half-life of AFP, and serum AFP level had reached at adult level after 8 months of age [7]. The measured half-life of AFP in normal infants was not rectilinear [8]. The difference in serum AFP levels between normal infants and patients who underwent surgery for SCT was not evaluated yet. In the current study, we investigated the half-life of AFP in SCT based on pathology and compared it with that of normal infants, available in the literature. We also aimed to confirm the value of AFP half-life as a predictor of SCT recurrence. 1. Materials and methods 1.1. Inclusion criteria Patients who were treated for SCT between 1997 and 2016 at the Asan Medical Center, Seoul, Korea were retrospectively reviewed. Neonates who underwent surgical treatment for SCT and had their serum AFP evaluated after surgery were included in the study. We excluded the patients who died before/after surgery, had malignant germ cell tumor, or had serum AFP check less than three times. The patients who had hepatic dysfunction or renal disease were excluded. During the study period, 70 patients with SCT were admitted to the neonatal intensive care unit. Five patients were excluded; one baby died before surgery, two patients died after surgery. One was confirmed as having yolk
https://doi.org/10.1016/j.jpedsurg.2018.08.012 0022-3468/© 2018 Elsevier Inc. All rights reserved.
Please cite this article as: Nam SH, et al, Half-life of alpha-fetoprotein in neonatal sacrococcygeal teratoma, J Pediatr Surg (2018), https://doi.org/ 10.1016/j.jpedsurg.2018.08.012
2
S.H. Nam et al. / Journal of Pediatric Surgery xxx (xxxx) xxx–xxx
Fig. 1. Study population ⁎: sacrococcygeal teratoma +: alpha-fetoprotein.
sac tumor, and one did not have N2 AFP values. Of the 65 patients, 10 exhibited recurrence, with 4 (40%) having yolk sac tumor (Fig. 1).
1.2. Data collection Medical records were retrospectively reviewed for gestational age, gender, birth weight, Apgar score, mother's age, delivery method, prenatal treatment, associated anomalies, age and body weight at surgery, operating time, and operative approach. To describe tumor biology, we collected the data for Altman classification, maximal diameter in preoperative imaging study, tumor diameter and weight after excision, and pathologic diagnosis.
1.3. Measurement of AFP and calculation of half-life Serum AFP was obtained from all patients prior to surgery. A protocol for AFP follow-up testing was lacking; however, AFP was measured every 1–3 months at outpatient clinics. The date of examination and the serum AFP values for the age of 2 years were collected. AFP was measured by a chemiluminescent microparticle immunoassay (CMIA) using an Abbott Architect Analyzer (Abbott Laboratories, Abbott Park, IL, USA). The half-life was calculated by the formula M = Mo × (1/ 2) Δt/T, where Mo is the baseline AFP concentration before surgery, M is the measured serum AFP after Δt days and T is the half-life. T is calculated using the formula T = Δt/Log 2 (Mo/M).
Fig. 2. Serum AFP levels between non-recurrent SCT and recurrent SCT ⁎: alpha-fetoprotein +: sacrococcygeal teratoma.
Please cite this article as: Nam SH, et al, Half-life of alpha-fetoprotein in neonatal sacrococcygeal teratoma, J Pediatr Surg (2018), https://doi.org/ 10.1016/j.jpedsurg.2018.08.012
S.H. Nam et al. / Journal of Pediatric Surgery xxx (xxxx) xxx–xxx
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Fig. 3. Half-life of AFP with reference to preoperative AFP in non-recurrent SCT ⁎: alpha-fetoprotein.
4.3 cm (range, 1.5–19 cm) as revealed by specimens. Forty one tumors were mature teratoma and 14 were immature teratoma.
1.4. Statistical analysis Linear regression analysis was conducted using the IBM SPSS Statistics software (version 20 for Windows; SPSS Inc., Chicago, IL), and the Chow test was used to compare linear regressions. P b 0.05 was considered statistically significant. The Sigma XL software (version 8, SigmaXL Inc., Kitchener, ON, Canada) was used to graph data with 95% confidence intervals (CI) and predictive intervals (PI). 2. Results 2.1. Clinical data Fifty-five non-recurrent SCT patients (M:F = 18:37) were enrolled. Mean gestational age was 37.5 ± 2.9 weeks and birth weight was 3,193.3 ± 641.1 g. Four babies underwent fetal intervention with radiofrequency ablation (RFA).They underwent surgery on average 7.4 ± 4.1 days after birth, and mean operating time was 150.5 ± 87.1 min. Standard posterior approach was possible in 52 patients, whereas 3 needed additional laparotomy. Altman tumor classification was as follows: type I lesions, 16 (29.1%); type II, 19 (34.5%); type III, 16 (29.1%); and type IV, 4 (7.3%). The tumor size was 7.4 ± 4.2 cm (range, 1.6–17 cm) as revealed by imaging, whereas it was 6.9 ±
2.2. Measurement and half-life of AFP Serum AFP was measured approximately 4.25 ± 2.07 times per patient within 2 years of age. The serum AFP of non-recurrent and recurrent tumors is indicated in Fig. 2; 165 half-lives were calculated. A significant correlation was observed between half-life and patient age using the formula (T1/2 = 0.0597 × days + 6.1643, R 2 = 0.4888, Durbin–Watson = 1.908, p b 0.001) (Fig. 3). A significant difference was observed between mature and immature SCT (p b 0.05). For mature SCT, half-life was calculated using the formula T1/2 = 0.0671 × days +4.3912, R 2 = 0.9042, Durbin–Watson = 2.064, p b 0.001), whereas for immature SCT, half-life was calculated using the formula T1/2 = 0.0433 × days + 8.9339, R 2 = 0.1336, Durbin–Watson = 2.222, p = 0.003 (Figs. 4 & 5). To compare the AFP half-life of the recurred tumor, we collected the serum AFP before the recurrence was confirmed. For recurrent SCT, halflife was calculated using the formula T1/2 = 0.1196 × days − 0.0633, R 2 = 0.3617, Durbin–Watson = 0.827, p b 0.001 (Fig. 6). A significant difference was shown between recurrent and non-recurrent SCT (p b 0.05).
Fig. 4. Half-life of AFP with reference to preoperative AFP in mature SCT ⁎: alpha-fetoprotein.
Please cite this article as: Nam SH, et al, Half-life of alpha-fetoprotein in neonatal sacrococcygeal teratoma, J Pediatr Surg (2018), https://doi.org/ 10.1016/j.jpedsurg.2018.08.012
4
S.H. Nam et al. / Journal of Pediatric Surgery xxx (xxxx) xxx–xxx
Fig. 5. Half-life of AFP with reference to preoperative AFP in immature SCT ⁎: alpha-fetoprotein.
3. Discussion AFP is a single chain glycoprotein; it is normally produced by the fetal yolk sac, liver, and gastrointestinal tract [10]. Serum AFP is elevated in cases of hepatic disorders, including acute hepatitis, liver cirrhosis, liver abscess, some hereditary disorders including ataxia telangiectasia and hereditary tyrosinemia type 1, and tumors, such as hepatocellular carcinoma, hepatoblastoma, germ cell tumors, pancreaticoblastoma, and retinoblastoma [6]. Secretion of AFP is also important for detecting malignant germ cell tumors with yolk sac tumor differentiation [3–6]. In cases of immature teratomas, AFP is elevated despite histologic examination being unable to detect the yolk sac tumor component [6]. AFP measurement is essential to evaluate the efficacy of germ cell tumor treatments and to predict tumor recurrence. During fetal period, AFP is primarily produced by the fetal yolk sac and liver [6,9]. After yolk sac degeneration, the fetal liver is the main site of AFP synthesis; thus, serum AFP is generally highly elevated in neonates (full-term neonates, 41,687 μg/L; preterm neonates, 158,125 μg/L) [9]. Serum AFP is gradually decline postnatally and it begins to disappear from blood 2 weeks after birth [6,7]. The time to reaching normal adult levels is unclear though it was reported between 8 months and 2 years old; therefore, we need to pay attention to
interpret serum AFP in infants. Even if high serum AFP levels are detected in infants, it is not always associated with hepatitis, malignant tumors or recurrence. It should be based on reliable reference of AFP in infants. The previous AFP reference in normal infants based on age was limited; it also showed a broad range of values in literature. Wu et al. reported that the AFP degradation half-life was 5.5 days between birth and 2 weeks after birth, 11 days between 2 weeks to 2 months after birth, and 33 days between 2 and 4 months of age after birth [7]. Blohm et al. reported different half-life ranges between term and premature babies. The half-life was longer in premature babies in the early period (5.1 vs. 6 days in first week) [9]. Ohama et al. calculated the half-life of AFP at every 10 days of age in normal infants. They observed that the half-life was 3 days at 10 days after birth, 21 days at 60 days after, and 42 days at 120 days after birth [8]. Using 524 blood samples of 390 normal infants, Blohm et al. observed that the AFP levels had not reached the adult serum AFP levels by the age of 2 years [9]. All three reports showed different references. Additionally, they had not obtained AFP serially in a single patient; however, they had collected the values in individuals. In the present study, we showed a linear relationship between postnatal age and serum AFP half-life using blood samples serially in a single
Fig. 6. The half-life of AFP with reference to preoperative AFP in recurrent SCT ⁎: alpha-fetoprotein.
Please cite this article as: Nam SH, et al, Half-life of alpha-fetoprotein in neonatal sacrococcygeal teratoma, J Pediatr Surg (2018), https://doi.org/ 10.1016/j.jpedsurg.2018.08.012
S.H. Nam et al. / Journal of Pediatric Surgery xxx (xxxx) xxx–xxx
patient after SCT surgery. Based on the formula for non-recurrent SCT in the present study (T1/2 = 0.0597 × days + 6.1643), the half-life in 2 weeks after surgery is 7 days; this value is higher than the range in normal infants in previous reports [7–9]. However, in our results, the half-life value obtained was 9.74 days in 60 days after surgery and 13.32 days in 120 days. This suggests that the half-life of SCT is quite different from that of the reference value in normal infants in previous studies. Kohn proposed that the clearance rate of a serum tumor marker after treatment could have prognostic significance [11], indicating that the tumor marker would be decreased after resection, and that the rate of decrease would be faster after tumor resection. A prolonged half-life may indicate the remaining or recurrent tumor, which continues to produce AFP even though it cannot be revealed in image study [4,12]. Thus, we compared the half-life of AFP between non-recurrent and recurrent SCT. SCT can potentially undergo malignant transformation. It can probably be detected early by regularly screening AFP and using imaging studies [10]. Here, we found that half-life of AFP in recurrent SCT exhibited a different formula; the half-life was shorter than that of nonrecurrent tumor in early postoperative period, but gradually it was getting longer over time until a recurrence was found. We're certain that a sudden increase in AFP might probably indicate recurrence; however, during the follow-up period, slow degradation of AFP could also predict recurrence. In such a case, plans for short-term follow-up can be made based on the obtained results. This study also has several limitations. First, it was a retrospective study, and the measurement interval was inconsistent. Second, we did not compare the half-life of AFP between SCT patients and normal infants, because the measurement of AFP was not included in routine check-up for neonatal intensive care. Third, we calculated the half-life based on the preoperative serum AFP as it was T0. Scheduled sampling requires a prospectively designed protocol. Also half-life Tn~n + 1 should be obtained from time tn to tn + 1. We included the levels of serum AFP within 2 years of age, because as reported in literature, the serum AFP did not decrease until 2 years after birth. Further, the recurrence observed in the current study occurred within two years after the operation. We did not find the reason for different half-life between mature teratoma and immature teratoma, and also we didn't compare the tumor characteristics between recurrent SCT and non-recurrent SCT. It requires further study. Despite these limitations, we could show the change of AFP half-life in patients with SCT, and could relate it to the
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tumor pathology and its recurrence. We hope that the results of the current study would serve as a meaningful guideline for AFP follow-up in SCT patients within 2 years of age. 4. Conclusion The half-life of AFP in neonatal patients with SCT was prolonged in proportion to the age, and it was getting longer in recurrent tumor than non-recurrent tumor. The half-life of AFP was longer in immature teratoma than in mature teratoma. Acknowledgment This work was supported by the Dong-A University research fund. References [1] Akinkuotu AC, Coleman A, Shue E, et al. Predictors of poor prognosis in prenatally diagnosed sacrococcygeal teratoma: a multiinstitutional review. J Pediatr Surg 2015;50:771–4. [2] Hambraeus M, Arnbjörnsson E, Börjesson A, et al. Sacrococcygeal teratoma: a population-based study of incidence and prenatal prognostic factors. J Pediatr Surg 2016;51:481–5. [3] Pauniaho SL, Tatti O, Lahdenne P, et al. Tumor markers AFP, CA 125, and CA 19-9 in the long-term follow-up of sacrococcygeal teratomas in infancy and childhood. Tumour Biol 2010;31:261–5. [4] Han SJ, Yoo S, Choi SH, et al. Actual half-life of alpha-fetoprotein as a prognostic tool in pediatric malignant tumors. Pediatr Surg Int 1997;12:599–602. [5] Keskin S, Ekenel M, Başaran M, et al. Predictive value of marker half-life in relapsed and nonrelapsed nonseminomatous germ cell testicular tumor patients undergoing chemotherapy. Am J Clin Oncol 2012;35:369–72. [6] Schneider DT, Calaminus G, Göbel U. Diagnostic value of alpha 1-fetoprotein and beta-human chorionic gonadotropin in infancy and childhood. Pediatr Hematol Oncol 2001;18:11–26. [7] Wu JT, Book L, Sudar K. Serum alpha fetoprotein (AFP) levels in normal infants. Pediatr Res 1981;15:50–2. [8] Ohama K, Nagase H, Ogino K, et al. Alpha-fetoprotein (AFP) levels in normal children. Eur J Pediatr Surg 1997;7:267–9. [9] Blohm ME, Vesterling-Hörner D, Calaminus G, et al. Alpha 1-fetoprotein (AFP) reference values in infants up to 2 years of age. Pediatr Hematol Oncol 1998;15:135–42. [10] Lahdenne P, Kuusela P, Siimes MA, et al. Biphasic reduction and concanavalin a binding properties of serum alpha-fetoprotein in preterm and term infants. J Pediatr 1991;118:272–6. [11] Kohn J. The dynamics of serum alpha-protein in the course of testicular teratoma. Scand J Immunol 8:103–7. [12] Shim JH, Han S, Lee YJ, et al. Half-life of serum alpha-fetoprotein: an early prognostic index of recurrence and survival after hepatic resection for hepatocellular carcinoma. Ann Surg 2013;257:708–17.
Please cite this article as: Nam SH, et al, Half-life of alpha-fetoprotein in neonatal sacrococcygeal teratoma, J Pediatr Surg (2018), https://doi.org/ 10.1016/j.jpedsurg.2018.08.012