Medical and Pediatric Oncology 32:436–437 (1999)
MISLEADING LEADS
Hereditary Persistence of Alpha-Fetoprotein in a Child With Testicular Germ
Cell Tumor
Pamela K. Cochran, BS,1 Allen R. Chauvenet, MD,1* P. Suzanne Hart, PhD,1
Siebold S.N. de Graaf, MD,2 Barbara Cushing, MD,3 Lawrence Kroovand, MD,4
and Marcia M. Wofford, MD1
Key words: germ cell tumor; alpha-fetoprotein; yolk sac tumor
Localized testicular germ cell tumors in children are
well known to be curable by surgery alone [1–3]. A
preliminary report of the Pediatric Oncology Group
9048/Children’s Cancer Group 8891 study indicated
82% event-free survival at 2 years in 65 testicular stage
I yolk sac tumors treated with surgery alone [4]. The 11
failures all appeared to have been salvaged with chemo-
therapy. Relapsed or persistent disease may first be de-
tected by an elevation of the alpha-fetoprotein (AFP), a
more sensitive indicator of recurrence than computed to-
mography (CT) [2,5]. Serial levels of AFP are followed
after surgery and usually recede to a normal value of less
than 10 ng/ml. Patients whose values do not fall into the
normal range or subsequently rise are presumed to have
persistent or recurrent disease and are treated with che-
motherapy. This routine, however, does not take into
account the presence of a rare disorder, hereditary per-
sistence of AFP [6–9], which could cause the patient to
continue to have elevated AFP levels despite the eradi-
cation of the tumor. We encountered such a case in which
a boy who underwent surgery for a testicular germ cell
tumor had persistent mild elevations of AFP and received
multiple courses of chemotherapy before it was discov-
ered that he had hereditary persistence of AFP (HPAFP).
The patient was a 20-month-old white male who un-
derwent a right lateral orchiectomy for a yolk sac tumor
invading the rete testis angiolymphatic spaces. The
proximal margin of the spermatic cord resection was
found to be free of tumor. The AFP level at the time of
surgery was 2,659 ng/mL. CT scans of chest/abdomen
and pelvis demonstrated no evidence of metastatic dis-
ease.
At this point, the child was referred to one of the
authors (LK), who performed a prophylactic transscrotal
orchipexy on the patient’s left testicle and followed AFP
levels. Three months later, the AFP had fallen to 61.34
ng/mL, but, with a half-life of 5 to 7 days, should have
been well within the normal range of <10 ng/mL by this
time [10]. During the next month, values ranged from
© 1999 Wiley-Liss, Inc.
98.34 to 152.90 ng/mL, leading to concern that there was
residual or recurrent tumor. Chemotherapy was started
with a regimen of cisplatin, bleomycin, and etoposide.
During treatment, all CT scans and physical examina-
tions remained negative for tumor. The first cycles of
chemotherapy, administered over 2 months, did not pro-
duce any significant change in the AFP levels. Figure 1
correlates treatments and AFP values.
Two weeks after completion of this therapy, the pa-
tient’s AFP level had risen to 79.03 ng/mL. Alternative
chemotherapy, using VAC (vincristine, actinomycin D,
and cyclophosphamide), was given for three courses be-
fore changing to ifosfamide and etoposide, as the VAC
did not appear to be effective. Two courses of these two
drugs were given, followed by alternating courses of
VAC and ifosfamide/etoposide. According to these AFP
results (Fig. 1), it did not appear that we were making any
progress against this residual disease; there remained no
evidence of clinical disease now 1 year after the initial
diagnosis and surgery.
Extensive consultations resulted in advice ranging
from exploratory laparotomy to “watch and wait” for the
tumor to show itself. Discussion of this case with one of
the authors (SH) led to investigation of parental AFP
levels. The mother’s was <3.0 ng/mL, but the father’s
1
Department of Pediatrics, Wake Forest University School of Medi-
cine, Winston-Salem, North Carolina
2
Pediatric Oncology Center, University Hospital Groningen, Gronin-
gen, The Netherlands
3
Children’s Hospital of Michigan, Detroit, Michigan
4
Department of Urology, Wake Forest University School of Medicine,
Winston-Salem, North Carolina
*Correspondence to: Dr. Allen R. Chauvenet, Department of Pediat-
rics, Wake Forest University School of Medicine, Medical Center
Boulevard, Winston Salem, NC 27157. E-mail: achauven@wfubmc.edu
Received 10 December 1998; Accepted 9 February 1999

Fig. 1. Serial AFP levels since surgery.
was found to be elevated at 21.40 ng/mL. This led to
testing of the paternal grandparents, revealing a level of
27.70 ng/mL in the paternal grandfather. Based on the
familial data, it was concluded that the patient has
HPAFP, of which there are only four other reported cases
in the literature [6–9]. HPAFP, discovered in settings
from antenatal screening to urologic procedures, is in-
herited as an autosomal dominant trait. The mild persis-
tent elevation of AFP does not appear to be associated
with abnormalities of any other serum proteins or to be
the cause of clinical disease.
Mutational analysis failed to reveal the previously de-
scribed mutation associated with HPAFP. In addition,
analysis of 1,264 base pairs of the AFP gene, including
exon 1, and 678 base pairs of the promoter has failed to
identify the mutation in this family.
To gain more information on the origin of the elevated
AFP levels in this family, serum samples from the pa-
tient, his father, and his paternal grandfather were sent to
the University Hospital in Groningen, The Netherlands.
Variations in the carbohydrate moiety of AFP from dif-
ferent sources result in different binding properties with
concanavalin A (con A) [11]. This heterogeneity can be
used to differentiate between elevated AFP from germ
cell tumor origin and elevated AFP due to benign or
malignant liver disease [12]. In all sera from the patient,
his father, and his grandfather, a high proportion of AFP
did not bind to con A, indicating a predominant germ cell
origin. Apparently, some genetic alteration causes their
germ cells to secrete increased amounts of AFP.
At this point, it was concluded that the patient’s mild
persistent elevation of AFP was due to the autosomal
dominant disorder HPAFP and not recurrent cancer. No
further interventions were attempted.
As of October 1998, the patient remains alive and well
with no evidence of recurrence, now 31 months follow-
ing his original diagnosis. His AFP levels continue to
range from 21.19 ng/mL to 82.42 ng/mL, all <100 ng/
Localized Testicular Germ Cell Tumors 437
mL, the arbitrary normal we have chosen for this child
(Fig. 1).
DISCUSSION
This child underwent three rigorous trials of chemo-
therapy, which in retrospect may not have been neces-
sary, before his unusual disorder was discovered. Though
this is probably a rare disorder, the incidence is not
known. It could be an explanation for a mild persistent
elevation of AFP following resection of localized germ
cell tumors. We propose that in similar situations, it
would be wise to check parental levels of AFP before
deciding on chemotherapy solely based on mildly el-
evated AFP. Compared to the cost and morbidity of che-
motherapy, this is a relatively simple and inexpensive
test that might save unnecessary exposure to potentially
toxic chemotherapy or other treatments.
ACKNOWLEDGMENTS
We thank Mr. H.G. Klip who performed the con A
assay at the Central Laboratory of the University Hospi-
tal Groningen.
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