Serum placental-type alkaline phosphatase activity in women with squamous and glandular malignancies of the reproductive tract

Abstract

To investigate serum placental-type alkaline phosphatase (PLAP-type) activities in women with squamous and glandular malignancies of the reproductive tract using an immunoradiometric assay.
PLAP-type immunoreactivity was measured in 180 women with non-ovarian malignancies of the reproductive tract and the values were compared with those from 334 controls. The cases comprised 18 vulval, nine vaginal, 103 cervical, 46 endometrial, and five fallopian tube cancers.
Serum PLAP-type activities were no different from controls in patients with squamous cell tumours. Women with adenocarcinoma of the cervix, endometrium, and fallopian tube had increased values: women with endometrial cancer had a median value nearly four times greater than that of controls. There was no direct correlation between PLAP-type activities and stage of disease in patients with endometrial cancer, but values reverted to normal after treatment.
Serum PLAP-type measurements are of no value in the management of patients with squamous cell tumours of the female reproductive tract. Raised activities can, however, be found in glandular tumours, in particular endometrial cancer where serum PLAP-type measurements may be of value in predicting remission.

Full text

doi:10.1136/jcp.47.11.1035
1994;47;1035-1037 J. Clin. Pathol.
Chard
T E Ind, R K Iles, P G Carter, D G Lowe, J H Shepherd, C N Hudson and T
malignancies of the reproductive tract.
activity in women with squamous and glandular
Serum placental-type alkaline phosphatase
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JT
Clin
Pathol
1994;47:1035-1037
Serum
placental-type
alkaline
phosphatase
activity
in
women
with
squamous
and
glandular
malignancies
of
the
reproductive
tract
T
E
J
Ind,
R
K
Iles,
P
G
Carter,
D
G
Lowe,
J
H
Shepherd,
C
N
Hudson,
T
Chard
The
Joint
Academic
Unit
of
Obstetrics,
Gynaecology
and
Reproductive
Physiology,
St
Bartholomew's
Hospital,
London
T
E
J
Ind
R
K
Iles
P
G
Carter
J
M
Shepherd
C
N
Hudson
T
Chard
Department
of
Histopathology
D
G
Lowe
Correspondence
to:
Dr
Thomas
Ind,
Williamson
Laboratory
for
Molecular
Oncology,
Department
of
Reproductive
Physiology,
St
Bartholomew's
Hospital,
51-53
Barts
Close,
West
Smithfield,
London
ECGA
7BE
Accepted
for
publication
24
March
1994
Abstract
Aim-To
investigate
serum
placental-
type
alkaline
phosphatase
(PLAP-type)
activities
in
women
with
squamous
and
glandular
malignancies
of
the
reproduc-
tive
tract
using
an
immunoradiometric
assay.
Methods-PLAP-type
immunoreactivity
was
measured
in
180
women
with
non-
ovarian
malignancies
of
the
reproductive
tract
and
the
values
were
compared
with
those
from
334
controls.
The
cases
comprised
18
vulval,
nine
vaginal,
103
cervical,
46
endometrial,
and
five
fal-
lopian
tube
cancers.
Results-Serum
PLAP-type
activities
were
no
different
from
controls
in
patients
with
squamous
cell
tumours.
Women
with
adenocarcinoma
of
the
cervix,
endometrium,
and
fallopian
tube
had
increased
values:
women
with
endometrial
cancer
had
a
median
value
nearly
four
times
greater
than
that
of
controls.
There
was
no
direct
correlation
between
PLAP-type
activities
and
stage
of
disease
in
patients
with
endometrial
cancer,
but
values
reverted
to
normal
after
treatment.
Conclusions-Serum
PLAP-type
mea-
surements
are
of
no
value
in
the
manage-
ment
of
patients
with
squamous
cell
tumours
of
the
female
reproductive
tract.
Raised
activities
can,
however,
be
found
in
glandular
tumours,
in
particular
endometrial
cancer
where
serum
PLAP-
type
measurements
may
be
of
value
in
predicting
remission.
(7
Clin
Pathol
1994;47:1035-1037)
Serum
measurement
of
placental
alkaline
phosphatase
(PLAP)
can
be
used
as
a
tumour
marker
for
testicular
and
ovarian
cancer.'
7
In
vitro
studies
have
shown
that
PLAP
is
also
produced
by
non-ovarian
malignancies
of
the
female
reproductive
tract.89
Several
groups
have
measured
PLAP
and
PLAP-like
material
in
the
serum
of
patients
with
non-ovarian
gynaecological
cancers,
but
the
results
have
been
conflicting.'0
16
A
possible
reason
for
the
divergent
results
was
that
most
groups
mea-
sured
the
intrinsic
alkaline
phosphatase
activity
of
the
protein,
and
this
may
be
defective
in
ectopically
produced
PLAP.17
18
In
addition,
factors
such
as
smoking,
ABO
blood
group,
and
menopausal
status
may
substantially
affect
circulating
concentrations.'8"23
We
re-evaluated
serum
PLAP-type
concen-
trations
in
women
with
non-ovarian
malig-
nancies
of
the
reproductive
tract
using
an
assay
that
measures
immunoreactivity
rather
than
enzymatic
activity.
Our
results
have
been
corrected
for
smoking
habits,
menopausal
sta-
tus,
and
ABO
blood
group.
Methods
One
hundred
and
eighty
patients
with
non-
ovarian
malignancies
of
the
female
reproduc-
tive
tract
had
blood
taken
before
treatment.
These
included
patients
with
vulval,
vaginal,
cervical,
endometrial,
and
fallopian
tube
can-
cers
(17,
nine,
103,
46,
and
five,
respectively).
In
14
cases
of
adenocarcinoma
of
the
cervix
and
endometrium
squamous
change
was
found,
and
these
patients
were
considered
separately
in
the
results.
A
further
14
samples
were
collected
from
the
same
patients
with
endometrial
cancer
fol-
lowing
treatment
and
a
period
of
remission.
Three
hundred
and
thirty
four
women
with
non-pregnancy
related,
non-neoplastic,
or
benign
neoplastic
gynaecological
disease
served
as
controls.
The
serum
PLAP-type
activities
in
some
of
the
control
group
have
been
reported
before.8
Samples
were
received
as
coded
specimens
and
stored
at
-
20°C.
PLAP-type
immunore-
activity
was
measured
by
immunoradiometric
assay
(IRMA).24
This
uses
the
monoclonal
antibody
H7
(InRo,
Sweden)
for
capture
and
H
1
7E2
(Unilever
UK)
for
detection.
The
IRMA
has
a
sensitivity
of
0-1
IU/l
and
has
no
cross-reactivity
with
intestinal
or
tissue
non-
specific
alkaline
phosphatase.
PLAP
values
were
measured
in
interna-
tional
units
and
expressed
as
multiples
of
the
regressed
control
group
median
(MoM)
after
correction
for
smoking,
ABO
blood
group
and
menopausal
status.
The
equation
used
was:
PLAP
=
10'-
0-065
-
(0.14
M
+
(0T35
h
S)
+
(0.018>
A)
+
(0.22X
B)
where
M
=
menopausal
status
(1
=
pre-
menopausal,
2
=
post-menopausal);
S
=
smoking
habits
(0
=
non-smoker,
1
=
smoker);
A
=
number
of
cigarettes
smoked
per
day;
and
B
=
ABO
blood
group
(1
=
blood
groups
A
and
AB,
2
=
0
and
B).
A
MoM
of
7X4
(100th
centile
for
controls)
was
used
as
a
cut
off.
PLAP
values
were
compared
1035
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Ind,
Iles,
Carter,
Lowe,
Shepherd,
Hudson,
Chard
Table
1
Serum
PLAP-type
activities
in
women
with
non-ovarian
malignant
disease
of
the
reproductive
tract,
and
statistical
comparison
with
the
control
group
of
334
women
Per
cent
Median
Range
Mann-Whitney
95%
CI
in
cases
positive
(MoM)
(MoM)
U
statistic
p
value
(controls)
Uterus
Adenocarcinoma
37
(13/35)
3-6
0-2-310
9203
<0
0001
07-4
9
Adenocarcinoma
with
squamous
change 18
(2/11)
5-2
12-46
6
3383
<0-0001
1-8-5-0
All
uterus
33
(15/46)
4-8
0-2-310
12972
<0-0001
1-29-4-56
Cervix
Squamous
3
(2/67)
1-2
0-2-13-2
14690
0-16
-0
1-0
4
Adenocarcinoma
3
(1/33)
1-6
0-2-7-8
7534
0
01
0-6-1.6
with
squamous
change
0
(0/3)
1.0
0-6-1-6
509
0.99
-0-4-0-6
All
cervix
3
(3/103)
1
2
0-2-13-2
25595
0
01
0
0-0
4
Vagina
Squamous
0
(0/8)
0
7
0-3-1-8
945
0-12
-0
9-0
1
Adenocarcinoma
0
(0/1)
14
-4
Allvagina
0
(0/9)
0-8
0-3-1-8
1180 0
21
-0-8-0-2
Vulva
Squamous
12
(2/17)
1.1
0-4-13
5
3630
0-12
-0
1-0
7
Fallopian
tube
Adenocarcinoma
40
(2/5)
6-6
2
5-50-1
1554
0-0012
1
5-947
Table
2
Serum
PLAP-type
concentrations
in
adenocarcinoma
of
the
cervix
and
endometium
by
stage
Median
MoM
Median
MoM
for
for
endometrial
adenocarcinoma
of
Stage
carcinoma
(n,
range)
the
cervix
(n,
range)
Unstaged
1-6
(7,
0-7-195)
Stage
1
1-7
(18,
0-2-310)
1
1
(16,
0-2-6-1)
Stage
2
6-9
(6,
1
1-94-1)
1-2
(2,
0-8-1-6)
Stage3
1
3(3,08-22)
1-9(2,0-7-3-1)
Stage
4
4-6
(6,
04-37-8)
1
1
(1,-)
New
recurrence
15
4
(6,
0-3-189)
3
0
(12,
02-7
8)
between
cases
and
controls
by
analysis
of
MoMs
using
the
Mann-Whitney
U
test.
Results
Serum
PLAP-type
activities
were
raised
in
patients
with
adenocarcinoma
of
the
cervix,
endometrium,
and
fallopian
tube
compared
with
controls
(table
1).
Values
were
no
differ-
ent
from
those
of
controls
in
patients
with
squamous
cell
carcinoma
of
the
lower
genital
tract
(table
1).
The
proportion
of
patients
with
increased
PLAP-type
values
was
highest
in
women
with
endometrial
and
fallopian
tube
cancers
(33
and
40%,
respectively)
(table
1).
Only
one
of
the
33
(3%)
patients
with
adeno-
carcinoma
of
the
cervix
had
circulating
con-
centrations
greater
than
the
100th
centile
for
controls,
but
the
median
concentrations
were
significantly
higher
than
those
in
the
controls
overall.
There
was
no
difference
in
circulating
PLAP-type
values
between
the
control
group
and
women
who
were
in
remission
after
treat-
ment
for
carcinoma
of
the
endometrium
(median
MoM
=
1-5,
u
=
2867,
p
=
0-25,
95%
confidence
interval
for
cases
and
con-
trols
=
-0-2
to
0-8,
respectively).
In
all
of
these
cases
serum
concentrations
had
fallen
and
were
below
the
100th
centile
for
controls.
No
correlation
with
stage
was
shown
in
patients
with
adenocarcinoma
of
the
cervix
or
endometrium
(table
2).
Discussion
These
results
clearly
show
that
serum
PLAP-
type
measurements
are
of
no
value
in
the
management
of
patients
with
squamous
cell
tumours
of
the
female
reproductive
tract.
Raised
values
can,
however,
be
found
in
some
glandular
tumours,
in
particular
endometrial
carcinoma.
Ectopic
production
of
a
PLAP-type
material
was
first
described
by
Fishman
et
al
in
1968.23
They
found
raised
values
in
a
man
with
carcinoma
of
the
lung.
Since
then,
PIAP
production
has
been
found
in
a
number
of
tumours,
of
which
ovarian
and
testicular
cancers
have
been
the
most
extensively
investigated.
1-6
11-16
22
26
32
However,
most
assays
for
PLAP-type
material
measure
the
enzymatic
activity
rather
than
protein
mass.
This
activity
may
be
defective
in
PLAP
expressed
in
neoplasms.
In
carcinoma
of
the
cervix
previous
studies
have
yielded
varying
results.
In
our
study
values
were
raised
in
glandular
but
not
squa-
mous
cell
tumours.
In
the
former,
activities
were
greater
than
the
100th
centile
for
the
control
group
in
only
3%
of
cases.
DeBroe
et
al
(1988)"
found
raised
PLAP-type
activity
in
7%
(five
of
70)
of
patients.
This
is
in
contrast
to
Doellgast
and
colleagues
(1984),26
who
found
raised
activities
in
41%
(28
of
69).
Other
groups
have
reported
that
between
15
and
25%
of
patients
have
increased
concen-
trations.'
12
1327
A
possible
reason
for
these
varied
results
is
the
use
of
different
cut
off
levels.
In
addition,
none
of
these
groups'
results
were
corrected
for
smoking
which
is
known
to
cause
a
10-fold
rise
in
serum
PLAP-
type
activities.
18-23
There
is
also
a
strong
association
between
smoking
and
the
develop-
ment
of
cervical
cancer
independent
of
PLAP-type
activity.
One
study
by
Muensch
et
al
(1986)22
excluded
smokers
and
found
raised
PLAP-type
activities
in
20%
of
patients
(one
of
five).
However,
the
small
number
of
patients
and
the
absence
of
histological
data
make
it
difficult
to
draw
conclusions
from
their
results.
Only
one
group
(DeBroe
et
al,
1988)"
have
measured
serum
PLAP-type
activity
in
patients
with
carcinoma
of
the
vulva
and
vagina.
In
that
study
concentrations
were
not
increased
in
any
of
their
eight
cases.
This
is
similar
to
the
present
data
for
PIAP-type
immunoreactivity.
No
group
has
reported
on
PIAP
activities
in
carcinoma
of
the
fallopian
tube.
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Serum
placental-type
alkaline
phosphatase
in
non-ovarian
malignancy
In
endometrial
carcinoma
we
have
shown
increased
activities
in
a
third
(14
of
46)
of
patients.
This
is
a
higher
proportion
than
that
found
in
studies
using
enzymatic
activity.
In
addition,
most
of
these
groups
have
used
a
lower
cut
off
level.
Cadeaux
et
al
(1974)27
found
raised
values
in
11%
(five
of
44)
and
DeBroe
et
al
(1988)"
in
19%
(10 of
54)
of
patients.
Two
other
groups
reported
increased
concentrations
in
15%
(eight
of
53)
and
9%
(seven
of
77)
of
patients.'
12
This
is
consistent
with
in
vitro
studies
which
showed
immuno-
reactive
but
not
enzymatically
active
PLAP
production
in
endometrial
tissue
cultures.9
Other
markers,
such
as
CA
125
are
raised
in
endometrial
cancer.
Kenemans
et
al
(1988)33
performed
a
meta-analysis
of
results
from
16
groups
and
found
high
CA
125
con-
centrations
(>35
U/ml)
in
27%
(66
of
245)
of
cases
of
endometrial
cancer.
However,
at
this
cut
off
level
CA
125
is
increased
in
20%
of
patients
with
benign
or
non-neoplastic
ovar-
ian
masses.33
In
our
study
we
used
a
cut
off
at
the
100th
centile
of
our
control
group
which
included
patients
with
benign
pelvic
masses.
Using
these
stricter
criteria,
we
suggest
that
PLAP-type
immunoreactivity
is
a
better
marker
for
endometrial
cancer
than
CA
125.
If
PLAP-type
material
is
to
be
a
useful
marker
in
the
management
of
endometrial
cancer,
a
correlation
with
tumour
bulk
and
spread
would
be
desirable.
In
this
respect
our
results
in
relation
to
the
stage
of
disease
are
clearly
disappointing.
However,
all
14
blood
samples
from
patients
in
remission
after
treat-
ment,
with
raised
PLAP-type
activities
before
treatment,
were
normal,
suggesting
that
this
test
may
be
of
value
in
determining
remission.
In
conclusion,
measurement
of
serum
PIAP-type
immunoreactivity
is
of
little
value
in
patients
with
squamous
cell
tumours
of
the
female
reproductive
tract
but
may
be
of
value
in
some
patients
with
glandular
malignancies.
This
study
was
supported
by
grants
from
the
St
Bartholomew's
Hospital
Cancer
Research
Committee
and
Joint
Research
Board.
Dr
T
Ind
is
a
recipient
of
an
Aylwen
Bursary.
1
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WH,
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NR,
Vaitukaitis
J,
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Pollet
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Schelstraete
JB,
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MW,
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Millan
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McLaughlin
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