Pediatric Hematology and Oncology, 18:11± 26, 2001

Copyright ° C 2001 Taylor & Francis

0888-0018/01 $12.00 + .00

Review Article

DIAGNOSTIC VALUE OF ALPHA1 -FETOPROTEIN AND BETA-HUMAN

CHORIONIC GONADOTROPIN IN INFANCY AND CHILDHOOD
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Dominik T. Schneider, MD h Clinic of Pediatric Hematology and Oncology,

Heinrich-Heine-University, Medical Center, DuÈ sseldorf, Germany, and Division of
Pediatric Pathology, Department of Pathology, Johns Hopkins Medical Institution,
Baltimore, Maryland, USA

Gabriele Calaminus, MD, and Ulrich Göbel, MD h Clinic of Pediatric

Hematology and Oncology, Heinrich-Heine-University, Medical Center,
DuÈ sseldorf, Germany

h This article provides a comprehensive review of the current literature and summarizes the expe-
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rience of the German cooperative protocols for nontesticular germ cell tumors (MAKEI) on the use of
alpha 1 -fetoprotein (AFP) and beta-human chorionic gonadotropin (b -hCG) for diagnostic evalua-
tion in pediatric oncology. Based on this evaluation, this review proposes guidelines for the initial
diagnostic work-up for children with clinically suspected secreting tumors. AFP and b -hCG represen t
the characteristic tumor markers of malignant epithelial liver tumors and malignant germ cell tumors
(GCT). They play an important role in the initial diagnostic evaluation as well as in the follow-up
examination during therapy. Current therapeutic strategies for both tumor types include preoperative
chemotherapy followed by delayed tumor resection. Therefore , it is essential for the pediatrician in
charge to be aware of the broad differential diagnosis of elevated AFP and b -hCG. In a well-de® ned
clinical setting, these tumor markers allow clinical diagnosis without histological con® rmation, but
the physiologically elevated AFP serum levels in infancy or unrecognized benign conditions, such as
hepatic diseases or hereditar y disorders , must also be considered as differential diagnoses. Therefore,
the laborator y investigations should include liver parameters in all patients to exclude hepatic dis-
ease. In addition, pregnancy must be excluded in adolescents. Careful history taking and clinical
examination will further help to rule out metabolic disorders or ataxia teleangiectasia that are as-
sociated with elevated AFP levels. Having excluded these conditions, elevated AFP levels above the
age-related normal range (with or without high b -hCG), indicate malignant epithelial liver tumors
in primar y liver lesions. At virtually all other sites, the diagnosis of a malignant GCT with a sub-
stantial yolk sac tumor and/or choriocarcinoma component can be established . Pancreaticoblastom a
should be considered in the differential diagnosis of tumors of the upper abdomen, and biopsy must be
performed. Other childhood tumors are rarely associated with AFP or b -hCG production, usually at

Received 28 March 2000; accepted 10 July 2000.

This work was supported by the Deutsche Krebshilfe e.V., Bonn, Germany. We thank Susanne Dippert
for her expert data management during the ongoing MAKEI and SIOP CNS GCT trials. We are grateful
to Michael Fritsch for his valuable contributions to this manuscript.
Address correspondence to D. T. Schneider, MD, Clinic of Pediatric Hematology and Oncol-
ogy, Heinrich-Heine-University, Medical Center, Moorenstr. 5, D-40225 DuÈ sseldorf, Germany. E-mail:
dominik.schneider@uni-duesseldorf.de

11
 12 D. T. Schneider et al.

only moderately elevated serum levels, and in most patients these tumors can be excluded by clinical
and radiological examination.

Keywords. AFP, b -hCG, diagnosis, review, tumor markers

Tumor markers can be measured in blood, cerebrospinal ¯ uid, or serous

effusions. Elevated levels are supposed to correlate with a malignant tumor.
Therefore, tumor marker evaluation has been applied for screening, diag-
nosis, and speci® cation of malignant tumors as well as for follow-up during
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and after therapy. However, in most instances tumor markers should be con-
sidered tumor-associated, rather than tumor-speci® c. This is particularly true
for the tumor markers alpha1 -fetoprotein (AFP), and beta-human chorionic
gonadotropin (b -hCG), although they are commonly regarded as the char-
acteristic tumor markers of malignant germ cell tumors (GCT) and epithelial
liver tumors. The signi® cant number of case reports on the association of
high AFP levels and a variety of tumors illustrates the diagnostic dilemma
of the interpretation of elevated AFP levels in neonates and young infants
[1± 7]. In childhood and adolescence, the spectrum of differential diagnoses
of patients with elevated AFP and/or b -hCG serum levels becomes even
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broader. For this paper we summarize and critically review the current liter-
ature concerned with the differential diagnosis of elevated AFP and b -hCG
in the pediatric population in order to develop diagnostic guidelines. The
proposed guidelines for initial diagnostic workup represent the experience
from the German protocol for nontesticular germ cell tumors.

ALPHA 1 -FETOPROTEIN
AFP is an oncofetal glycoprotein with a molecular weight of 68,000 Da.
During embryo- and fetogenesis AFP is produced in the yolk sac, the liver,
and the gastrointestinal tract [8, 9]. During early pregnancy AFP is the pre-
dominating serum protein, showing maximum fetal serum levels of 3± 4 g/L
in the 12th week of pregnancy. As AFP crosses the placenta it can be meas-
ured in the serum of the pregnant mother. While the maternal serum levels
usually remain below 500 l g/L, higher AFP levels may indicate fetal malfor-
mations, fetal distress, or malnutrition. Therefore, AFP measurements have
been broadly utilized in pregnant women [10, 11].
In neonates, the AFP serum levels are highly elevated (term neonates:
41,687 l g/L, preterm neonates: 158,125 l g/L; median levels) [12]. In most
infants, the AFP serum levels decrease to normal adult levels within the ® rst
10 months, but in a signi® cant proportion of children AFP levels do not
normalize until the end of the 2nd year of life [12]. This time course of
AFP reported by our study group stands in some contrast to previous reports
on normal AFP levels in infants [13]. On the other hand, the experience
 AFP and hCG in Childhood and Adolescence 13

from the German GCT protocols and another recent report substantially
support our observation that AFP may be physiologically elevated in a larger
proportion of infants than reported previously [14].
Immunoelectrophoresis allows distinguishing between distinct subfrac-
tions of AFP that differ in their carbohydrate component and in their lectin
binding properties. Therefore, it has become possible (in an experimen-
tal rather than clinical setting) to distinguish between AFP elevation arising
from benign liver disorders, malignant liver tumors, and yolk sac tumors
[15, 16].
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Elevated AFP Associated with Benign Conditions

Elevated AFP serum levels are most commonly found in acute liver dis-
orders (Table 1), and in most patients AFP levels remain below 500 l g/L
[15, 17, 18]. The data on the prognostic value of high AFP levels in hepati-
tis are still contradictory. One study reported that in acute hepatitis, high
AFP levels correlate with a severe clinical course and derangement of liver
function, whereas recovery is predicted by a decrease of serum AFP [19].
In chronic hepatitis, AFP elevation is associated with positivity for hepatitis
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B surface antigen and elevation of transaminases [20]. On the other hand,

high AFP levels correlate with survival of patients with fulminant hepatitis,
and it is assumed that AFP may re¯ ect hepatocellular regeneration [21, 22].
TABLE 1 Elevated AFP Associated with Benign Conditions

Disease AFP level Frequency (%) References

Hepatic disorders
Extrahepatic biliary atresiaa +± + + + 75 Johnston [76], Saito [77]
Neonatal hepatitisa +± + + 66 Johnston [76], Saito [77]
Acute and chronic viral +± + + · 45 Bloomer [18], Lamerz [17],
hepatitis (B and C) Liaw [20]
Fulminant acute hepatitis +± + + · 50 Jain [19], Pastore [21, 22]
Liver cirrhosis +± + + · 15 Bloomer [18], Lamerz [17]
Liver abscess (pyogenic, amebic) +± + + 7 Amanjee [78], Sharma [79]
Hereditary disorders
Hereditary AFP persistence +± + + Case report Feng [27], Greenberg [28],
Cochran [26], Schefer [29]
Ataxia telangiectasia +± + + + > 90 Woods [24], Cabana [23]
Hereditary tyrosinemia type 1 +± + + + > 90 Pitkanen [35]
Miscellaneous
Systemic lupus erythematosis +± + + 20 Wollina [55]
Hirschsprung’s diseasea n.d.
Pregnancy +± + + 100 Lamerz [10], Waller [11, 80]
Infancy +± + + + 100 Blohm [12], Ohama [14],
Gale [13], Wu [81],
Tsuchida [82]

Note. + , · 100 l g/L; + + , · 1000 l g/L; + + + , > 1000 l g/L.

a In these reports of neonatal disorders, it was unclear whether the reported AFP levels remained within

the age-related normal levels.

 14 D. T. Schneider et al.

In addition, there are some hereditary disorders that are associated with in-
termittent or persistent AFP elevation. In ataxia telangiectasia, which is asso-
ciated with an increased risk of malignant tumors such as Hodgkin disease,
elevated AFP is considered a diagnostic criterion [23]. AFP subfractiona-
tion revealed that AFP is produced in the liver [24, 25]. Therefore, ataxia
telangiectasia patients with a mediastinal tumor and moderately elevated
AFP levels are more likely to have Hodgkin lymphoma than malignant GCT,
and biopsy is indicated. In other disorders, such as hereditary tyrosinemia,
metabolic crises are associated with a substantial increase of AFP.
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There have been some rare reports of hereditary persistence of AFP

[26± 29], and in one family this was attributed to a point mutation within the
AFP gene [30]. However, only one patient with a GCT and hereditary per-
sistence of AFP has been reported to date [26]. Chronic renal insuf® ciency
does not interfere with AFP serum levels [31]. Other benign disorders in
which elevated AFP levels have been reported are summarized in Table 1.

Elevated AFP Associated with Tumors (Table 2)

Liver Tumors
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AFP is the characteristic tumor marker of hepatocellular carcinoma

(HCC) in adults and of hepatoblastoma (HB) in children [10, 17, 32± 34].
Regular serum AFP monitoring is recommended for patients at high risk for
HCC, such as those with chronic hepatitis or cirrhosis, because an increase

TABLE 2 Elevated AFP Associated with Malignant Tumors

Disease AFP level Frequency (%) References

Hepatic epithelial tumors

Hepatoblastoma +± + + + > 70 von Schweinitz [33, 34]
Hepatocellular carcinoma +± + + + > 90 von Schweinitz [33, 34], Pavesi [83],
Lamerz [17]
Germ cell tumors
Yolk sac tumor +± + + + > 90 GoÈ bel [64]
Immature teratomaa +± + + < 20 GoÈ bel [47, 64]
Miscellaneous pediatric tumors
Pancreaticoblastoma +± + + + Case reports Iseki [49], Willnow [50]
Retinoblastoma + 18 Minei [84]
Teratomatous nephroblastoma ++ Case reports Ashworth [51], Patriarca [44],
Roth [52]
Tumors in adult patients
Adenocarcinoma of the +± + + + · 20 Sawada [43], Kodama [38],
gastrointestinal tract Kubo [39], Cocquyt [37]
Bronchial carcinoma +± + + + · 20 Asamura [36], Miyake [85],
Yoshimoto [40]
Bladder carcinoma ++ Case report Takayama [42]

Note. + , · 100 l g/L; + + , · 1000 l g/L; + + + , > 1000 l g/L.

a In most cases, microscopic foci of yolk sac tumor can be demonstrated by immunohistochemistry [48].
 AFP and hCG in Childhood and Adolescence 15

of AFP may identify the development of HCC early [10, 17]. In infants, AFP
measurements help to distinguish between HB and hepatic infantile heman-
gioblastoma or liver metastasis of other tumors such as neuroblastoma [34].
In children with HB, AFP seems to be prognostically signi® cant, since it could
be demonstrated that children with either low AFP (< 100 l g/L, usually asso-
ciated with histological dedifferentiation) or very high AFP ( >100,000 l g/L,
usually indicative for large tumor volume) have a signi® cantly worse outcome
than others [33]. Children with hereditary tyrosinemia type I are at high
risk of developing HCC [35]. In these patients, serial evaluation of AFP is
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complicated due to intermittent metabolic crises with simultaneous rise of

AFP levels [35]. Furthermore, other tumor markers such as carcinoembry-
onic antigen (CEA) are not useful, because they may also be elevated [35].
Therefore, the value of serological screening for HCC is compromised in
these patients, and other investigations such as ultrasound examinations are
more useful.
In approximately 20% of adult gastrointestinal or bronchial carcinoma
and rarely in other tumors, AFP may be elevated, sometimes in association
with liver metastasis [17, 36± 44]. In some tumors AFP production seems to
be associated with a hepatoid differentiation pattern, and AFP production
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in the tumor cells can be visualized by immunohistochemistry [37, 41]. Fur-

thermore, there is experimental evidence that some AFP-producing tumors
have an increased potential of liver metastasis [45]. However, these tumors
are only rarely found in the pediatric cohort, and therefore, they are not a
prominent consideration in the differential diagnosis of elevated AFP in pe-
diatric patients. In addition, the simultaneous evaluation of CEA may further
help to establish the diagnosis, because CEA will be elevated in the majority
of these tumors [43, 46].

Gonadal and Nongonadal Yolk Sac Tumors

AFP secretion is characteristic for malignant GCT with yolk sac tumor
(YST) differentiation. Thus, the evaluation of AFP in serum, cerebrospinal
¯ uid, or serous effusions aids in establishing diagnosis. In some tumors, es-
pecially immature teratomas, the histological examination may show no evi-
dence of YST despite elevated serum AFP levels. In biopsies of large tumors,
the lacking histological evidence of YST can be explained by sampling errors,
but in many cases the immature teratoma includes microscopic foci of YST,
which may be recognized by immunohistochemistry only [47, 48]. There-
fore, evaluation of serum AFP prior to surgery is mandatory in all children
with suspected malignant GCT or teratoma, because it is complementary to
the histological examination. This is particularly true for intracranial GCT,
because in many patients only a limited (stereotactic) biopsy will be obtained.
Because the prognosis of intracranial secreting GCT is inferior compared to
intracranial germinoma, it is recommended to treat patients with elevated
tumor markers in serum or cerebrospinal ¯ uid according to protocols for
 16 D. T. Schneider et al.

secreting malignant GCT, even despite contradicting histology (for example,

see the current SIOP CNS GCT 96 protocol).
There are other rare tumors in childhood that are associated with ele-
vated AFP serum levels. Among these, pancreaticoblastoma is most common
[49, 50]. Since it may be impossible to distinguish between pancreaticoblas-
toma, primary retroperitoneal GCT, and retroperitoneal metastases of small
distant AFP-positive tumors (HB, HCC, GCT), a biopsy of the tumor is in-
dicated at this speci® c tumor site. Apart from rare case reports of nephro-
blastoma showing partly cystic or teratomatous differentiation, there are no
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other reports of AFP-positive tumors of mesodermal origin [44, 51, 52].

BETA-HUMAN CHORIONIC GONADOTROPIN (¯ -hCG)

Human chorionic gonadotropin (hCG) is a glycoprotein with a molecu-
lar weight of 38 kD. It consists of two polypeptide chains. The alpha chain
shows a high sequence homology to other pituitary hormones, including
luteinizing hormone, follicular stimulating hormone, and thyroid stimulat-
ing hormone, whereas the amino-terminus of the beta chain is partly homol-
ogous to the beta chain of luteinizing hormone. There are several commer-
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cially available radioimmunoassays capable of detecting either whole hCG

or its beta chain (b -hCG). b -hCG serum concentrations above 10 IU/L are
regarded as elevated.
b -hCG is physiologically produced in the placenta and serves to sustain
the corpus luteum in early pregnancy. In pregnancy, if abundant b -hCG
levels do not decline in the second trimester, this may indicate trophoblastic
proliferative disorders, such as hydatidiform mole or choriocarcinoma [53].
In combination with AFP, b -hCG has been used as a screening method for
fetal disorders such as trisomy 21 [53].

Elevated ¯ -hCG Associated with Benign Disorders

There are only a few benign disorders in which an association with

elevated b -hCG levels has been reported. Among these, chronic renal in-
suf® ciency is probably most frequent. In one study of patients receiving
dialysis treatment, elevated b -hCG levels (up to 10 times normal levels)
have been found [54]. This observation is explained by the impaired re-
nal clearance of a faint background production of b -hCG. Others have
found elevated b -hCG levels in 24% of patients with systemic lupus erythe-
matosis, and in some patients simultaneous elevations of the tumor marker
CA125 were observed [55]. In these patients autoantibodies against ovarian
and/or endometrial antigens can be detected, and it is concluded that these
patients may suffer from a de® ned autoimmunological± endocrinological
syndrome [56].
 AFP and hCG in Childhood and Adolescence 17

Elevated ¯ -hCG Associated with Tumors

b -hCG is clearly associated with trophoblastic differentiation of both
pregnancy-associated and de novo germ cell tumors, and immunohistochem-
istry easily detects b -hCG production in trophoblastic and syncytiotropho-
blastic cells [48, 53]. In some choriocarcinomas, the histologic evaluation
may be complicated by extensive hemorrhagic necrosis. In these patients,
the serological detection of b -hCG is of vital importance [57]. Therefore,
the serological detection of b -hCG supports a diagnosis of malignant GCT
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and proves the presence of trophoblastic cells even in the absence of de® ni-
tive histology. b -hCG elevation has also been observed in some large his-
tologically pure germinomas (testicular seminoma, ovarian dysgerminoma,
intracranial germinoma), but in most patients the b -hCG levels remain below
200 IU/L [58± 60]. In these patients, free beta chains of hCG are secreted
[59], and b -hCG production is detected in scattered syncytiotrophoblastic
giant cells [61]. It remains debated whether patients with seminoma and
elevated b -hCG represent a distinct clinical and prognostic subgroup, but a
recent large prospective analysis does not support this hypothesis [60].
In conclusion, patients with histologically proven pure germinomas and
slightly elevated b -hCG can be treated according to the corresponding germi-
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noma protocols. In the current international SIOP CNS GCT 96 protocol for
intracranial GCT and in the German MAKEI protocols for extracranial GCT
an upper limit for b -hCG value of 50 IU/L is recommended. b -hCG can also
be elevated in hepatoblastoma or hepatocellular carcinoma. Again, syncyt-
iotrophoblastic giant cells with immunohistochemical evidence of b -hCG
production can be demonstrated in these tumors [62, 63]. In adult pa-
tients, b -hCG production can be detected in a substantial proportion of solid
tumors, most of which represent poorly differentiated adenocarcinoma of
the gastrointestinal tract (Table 3).

DISCUSSION
Guidelines for Initial Diagnosis
It is obvious from the above data that AFP and b -hCG are not suitable
for population-wide screening for secreting malignant tumors. In addition,
the experience from the MAKEI protocols and this review of the current
literature makes it apparent that elevated AFP and b -hCG levels by themselves
do not allow for a clinical diagnosis of tumor. Additional examinations must
complement tumor marker evaluation. First, AFP serum levels must care-
fully be compared to the age-related reference values in infants. As discussed
above, the previously reported AFP reference values may be inappropriate
for some patients. Therefore, in infants with a tumor and slightly elevated
AFP levels a histological diagnosis should be obtained or the time course of
 18 D. T. Schneider et al.

TABLE 3 Elevated b -hCG Associated with Malignant Tumors

Disease b -hCG level Frequency (%) References

Germ cell tumors

Choriocarcinoma +± + + + > 90 GoÈ bel [64]
Seminoma, dysgerminoma, + 10 GoÈ bel [64], Mann [59],
germinoma Weissbach [60]
Hepatic epithelial tumors
Hepatoblastoma +± + + + 18 Nakagawara [62], Watanabe [63],
von Schweinitz [34]
Hepatocellular carcinoma +± + + + 22 Scheuer [86], Nakanuma [87]
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Miscellaneous tumors in
adolescents and adults
Osteogenic sarcoma +± + + + Case report Kalra [88]
Gastric carcinoma + <5 Rau [89]
Cholangiocarcinoma +± + + · 85 Alfthan [90], Fukuda [91]
Pancreatic carcinoma +± + + · 72 Alfthan [90]
Islet cell adenoma in +± + + · 75 Stock [92]
MEN I syndrome
Prostatic carcinoma +± + + Case report Broder [93]
Breast carcinoma +± + + + · 13 Caf® er [94]

Note. + , · 100 IU/L; + + , · 1000 IU/L; + + + , > 1000 IU/L.

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AFP should be evaluated until invasive treatment is started. Other conditions

that may be associated with elevated AFP and/or b -hCG must be excluded.
Evaluation of liver enzyme levels helps to exclude the most frequent causes
of elevated AFP. Most of the other disorders listed in Table 1 may be ex-
cluded by careful history taking and clinical examination. Pregnancy must
be excluded in adolescent girls with elevated AFP and/or b -hCG levels. In
most of the benign conditions, tumor markers will be only slightly elevated.
In our experience, serum levels above 500 l g/L for AFP or 500 IU/L b -hCG
are rarely associated with a benign diagnosis.
Due to the high incidence of nongonadal GCT, the speci® c tumor site
and radiographic examination may further help to establish the correct clin-
ical diagnosis. In gonadal tumors with elevated AFP and/or b -hCG levels,
malignant GCT with either YST or choriocarcinomatous differentiation are
the diagnoses to consider. Nevertheless, b -hCG may be slightly elevated in
some large seminomas with scattered syncytiotrophoblastic giant cells. In the
sacrococcygeal region, virtually all malignant GCT show YST differentiation,
either as pure YST or as mixed GCT with a YST component, and AFP will
be elevated above the age-related reference levels in most patients. Sacro-
coccygeal choriocarcinoma is very rare (< 1% of the German series). Other
relevant nongonadal sites of GCT include the mediastinum and the brain.
At both sites, elevation of one or both tumor markers clearly indicates a ma-
lignant GCT, because in the pediatric cohort there are no other malignant
tumors associated with AFP and/or b -hCG elevation (Tables 2 and 3). There
have been some reports of high AFP levels associated with a variety of benign
 AFP and hCG in Childhood and Adolescence 19

and malignant tumors, but the age-related reference values of AFP were
underestimated in most of these reports [1± 7]. Because of possible discor-
dance, a measurement of tumor markers in both serum and cerebrospinal
¯ uid is mandatory in intracranial GCT. Thus, incorrect diagnosis due to
incomplete sampling can be avoided.
In primary hepatic tumors with elevated AFP, the diagnosis of HB or HCC
is most likely because primary hepatic GCT are very uncommon [64]. The
data from the literature suggest that a simultaneous elevation of both AFP
and b -hCG occurs at a comparable frequency in both HB and HCC (Table 3).
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In tumors of the upper retroperitoneum, elevated AFP levels do not allow an

unequivocal diagnosis, because retroperitoneal GCT, pancreaticoblastoma,
and metastasis of HB/HCC must all be taken into account. In this situation,
biopsy of the tumor is indicated.

Examination of AFP and/or ¯ -hCG Positive Tumors During Therapy

Tumor marker follow-up examinations may be performed in two distinct
clinical settings: First, they can occur after surgical removal of a localized tu-
mor (watch-and-wait strategy). In this setting, a decrease of the tumor mark-
ers slower than their physiological half-lives (AFP: < 6 days, b -hCG: < 1 day)
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indicates residual or recurrent tumor, and a clinical restaging is indicated.

Second, tumor markers can be measured repeatedly during chemotherapy
prior to a delayed tumor resection. In both clinical settings, the tumor mark-
ers must be measured in at least weekly intervals until normalization, and
in stepwise increasing intervals thereafter. In patients treated with primary
chemotherapy, the decline of the tumor markers helps to evaluate tumor
response to chemotherapy. It was demonstrated for both adult and pedi-
atric GCT, that a slow decrease of AFP (half-life > 6± 7 days) and of b -hCG
(half-life > 3.5± 4 days) predicts a highly signi® cantly increased risk of tu-
mor relapse [65± 67]. In our experience, it has proven useful to compare
the decline of AFP during the ® rst weeks of chemotherapy to the course
of AFP in term neonates (Figure 1) [67]. Finally, it should be considered
that in large tumors, a reversible increase of AFP levels after initiation of
chemotherapy may occur, which seems to be due either to liberation of AFP
from necrotic tumor cells or to liver dysfunction under therapy (Figure 1c)
[68, 69].
There are rare patients with mixed GCT, in whom the radiographic and
serological ® ndings are discordant, showing an increase in tumor size de-
spite decreasing tumor markers (Figure 1d). These patients resemble the so-
called growing teratoma syndrome in which mature or immature teratoma
components continuously proliferate while the YST component responds
to chemotherapy. An immediate surgical removal of the tumor is urgently
indicated [70± 72].
 20 D. T. Schneider et al.
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FIGURE 1 Illustration of AFP in 4 patients with malignant GCT in comparison to the physiological
decline of AFP in term neonates (gray: median, 5 and 95 percentile) [12]. (a) 3-year-old girl with sacro-
coccygeal YST. Macroscopically incomplete tumor resection followed by cisplatinum chemotherapy. Ade-
quate AFP decline (t1 / 2 < 6 days). (b) 16-year-old girl with ovarian YST. Tumor resection, watch-and-wait
strategy. Delayed diagnosis of relapse due to misinterpretation of AFP (weeks 5 to 10). Relapse with massive
peritoneal carcinomatosis. Initial reversible increase of AFP after initiation of cisplatinum chemotherapy
followed by adequate decline of AFP (t1 / 2 < 6 days). (Continued)
 AFP and hCG in Childhood and Adolescence 21
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FIGURE 1 (Continued)(c) 7-year-old girl with ovarian yolk sac tumor. Adequate AFP decline despite
initial increase of AFP levels from 500 to 686 l g/L during the ® rst week of chemotherapy. Complete
tumor resection after preoperative chemotherapy. (d) 15-year-old boy with mediastinal GCT (needle
biopsy: immature teratoma). Continuous but inadequate decline of AFP under primary cisplatinum
chemotherapy, simultaneous signi® cant tumor progression (ªgrowing teratoma syndromeº). Complete
clinical and serological remission after tumor resection.
 22 D. T. Schneider et al.

CONCLUSION
After exclusion of rare benign conditions associated with tumor marker
secretion, AFP and b -hCG levels are of high differential diagnostic value for
tumors at all sites apart from the upper retroperitoneum where a tumor
biopsy is advisable. Thus, evaluation of AFP and b -hCG aids in the immedi-
ate establishment of neoadjuvant therapies for secreting tumors. It has been
demonstrated that a neoadjuvant strategy helps to promote surgical radical-
ity on delayed tumor resection, to avoid mutilating surgery and to obtain
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an improved relapse free survival [73± 75]. Furthermore, the decrease of the
tumor marker levels during preoperative chemotherapy allows for evalua-
tion of tumor response to chemotherapy, and may further help to de® ne
prognostic subgroups [65± 67].

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