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Int. J. Cancer (Pred. Oncol.): 84, 525–528 (1999)
r 1999 Wiley-Liss, Inc.
Publication of the International Union Against Cancer
Publication de l’Union Internationale Contre le Cancer
CONCENTRATION OF FREE hCG␤ SUBUNIT IN SERUM AS A PROGNOSTIC
MARKER FOR SQUAMOUS-CELL CARCINOMA OF THE ORAL CAVITY AND
OROPHARYNX
Johan HEDSTRÖM1*, Reidar GRENMAN2, Hans RAMSAY1, Patrik FINNE3, Johan LUNDIN4, Caj HAGLUND5,
Henrik ALFTHAN3 and Ulf-Håkan STENMAN3
1Department of Otorhinolaryngology, University of Helsinki, Helsinki, Finland
2Department of Otorhinolaryngology-Head and Neck Surgery and Medical Biochemistry, University of Turku, Turku, Finland
3Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland
4Department of Oncology, University of Helsinki, Helsinki, Finland
5Department of Surgery, University of Helsinki, Helsinki, Finland
This study was conducted to evaluate the clinical usefulness
of serum hCG␤ in the diagnosis and prognosis of patients (n ⴝ
59) with cancers of the oral cavity and oropharynx. As a
reference marker we used squamous-cell carcinoma antigen
(SCCAg). A blood sample was obtained from all patients
before primary surgery. Serum hCG␤ was determined by a
time-resolved immunofluorometric assay (IFMA) and SCCAg
by a solid phase immunoenzymometric assay. Elevated preoperative hCG␤ levels were observed in 8 (14%) and elevated
SCCAg in 12 (20%) out of 59 patients. Patients with preoperatively elevated hCG␤ had a shorter recurrence-free survival
when compared with those with normal hCG␤ levels (logrank Chi-squared ⴝ 6.83, p ⴝ.009), and the risk-ratio for
recurrence during follow-up for those was 3.6 (95% CI ⴝ
1.29–9.94). In a Cox multivariate model hCG␤ (p ⴝ 0.039)
and stage (p ⴝ 0.044) were independent prognostic factors.
SCCAg showed no correlation with recurrence-free survival.
We conclude that determination of hCG␤ in serum is a
potential marker in the prognostic evaluation of patients with
SCC of the oral cavity and oropharynx. Int. J. Cancer (Pred.
Oncol.) 84:525–528, 1999.
r 1999 Wiley-Liss, Inc.
Head and neck cancer is the sixth most common type of cancer in
the world (Åkervall, 1998). Histopathologically, squamous-cell
carcinoma (SCC) is by far the most frequent histological type of
this disease (Rassekh et al., 1994). After curative treatment, about
50% of the patients develop a recurrence, and 80% of the relapses
occur within the first 2 years of follow-up (Terhaard et al., 1992).
About 50% of the patients with SCC of the head and neck
(SCCHN) die from cancer with no significant improvement during
recent decades (Rassekh et al., 1994).
In the management of patients with SCCHN, treatment decisions
are still based on the TNM classification system, although T and N
status do not reliably predict the clinical outcome in individual
cases (Bailey, 1991; Hanna et al., 1990). Thus, effective treatment
planning would be enhanced by identification of prognostic
indicators that would reflect the biological behavior of a tumor. The
identification of a reliable circulating tumor marker therefore has
great potential. Although new potential prognostic markers are
continuously being introduced and evaluated in SCCHN, so far
none has influenced standard treatment (Rassekh et al., 1994;
Hanna et al., 1990; Snyderman et al., 1995).
Human choriogonadotropin (hCG) is a glycoprotein hormone
produced by the placenta. It is widely used for diagnosis of
pregnancy, pregnancy-associated disorders and trophoblastic disease. hCG consists of 2 dissimilar subunits designated ␣ and ␤.
During pregnancy, the proportion of hCG␤ is 1 to 5% of hCG
immunoreactivity, and in healthy nonpregnant subjects, the proportion of hCG␤ to hCG is 10 to 30% (Alfthan et al., 1992a,b). In
gestational trophoblastic disease, the serum and urine levels of
hCG␤ are almost always elevated (Fan et al., 1987), and elevated in
35% in testicular cancer (Saller et al., 1990). In nontrophoblastic
cancers, elevated levels have most often been observed in patients
with tumors of the pancreas (30–72%) (Marcillac et al., 1992;
Alfthan et al., 1992b), stomach (9%) (Marcillac et al., 1992), and
liver (11%) (Marcillac et al., 1992), in gynecological cancers
(26%) (Marcillac et al., 1992) and in bladder cancer (35–47%)
(Marcillac et al., 1992; Iles et al., 1996). In urothelial and ovarian
cancer determination of hCG␤ is of prognostic value (Iles et al.,
1996; Ind et al., 1997). hCG␤ expression has been identified in 29
of 45 (64%) of SCC from the oral cavity (Bhalang et al., 1999),
indicating that hCG␤ is produced by the majority of these tumors.
One study was conducted to determine serum concentration of
hCG␤ in head and neck cancer. In this study, all 7 patients showed
hCG␤ levels below the detection limit of the assay (Marcillac et al.,
1992).
We have now studied whether hCG␤ has any diagnostic and
prognostic value in the evaluation of patients with cancer of the
oral cavity and oropharynx. As a reference marker, we used
squamous-cell-carcinoma antigen (SCCAg), one of the few useful
markers for patients with SCC of the head and neck (Eibling et al.,
1989; Snyderman et al., 1995). Among different forms of SCC of
the head-and-neck region, tumors of the oral cavity and oropharynx
are particularly associated with poor prognosis. We therefore
included only patients with tumors of this type.
MATERIAL AND METHODS
Patient samples
The study included 59 consecutive patients presenting with SCC
of the oral cavity or oropharynx admitted to the Department of
Otorhinolaryngology—Head-and-Neck Surgery of Turku University Central Hospital between 1989 and 1996 (Table I). All these
patients underwent surgery, and 50 patients (85%) received radiation therapy. A blood sample was obtained from each patient before
surgery and before radiation therapy. Of the patients, 27 were
female and 32 male. Ages ranged from 37 to 92 years, with a mean
of 67 years. Tumor histology, site, stage, grade, and recurrences
were analyzed; 38 patients (64%) showed no recurrence within the
follow-up period that ranged from 14 to 93 months (median 33
months). The follow-up program included clinical evaluation and,
when indicated, endoscopic examination every third month for 2
years, and thereafter during 1 to 3 annual follow-up visits.
Recurrences were detected in 21 patients (36%), and 7 patients
Grant sponsors: Research Foundation Finska Läkaresällskapet, Research
Foundation Liv och Hälsa and Research Institute, Helsinki University
Central Hospital.
*Correspondence to: Department of Otorhinolaryngology, Helsinki University Central Hospital, FIN-00290 Helsinki, Finland. Fax: ⫹358–04714804. E-mail: johan.hedstrom@huch.fi
Received 29 March 1999; Revised 5 June 1999
HEDSTRÖM ET AL.
526
TABLE I – SITE, STAGE AND GRADUS OF 59 PATIENTS WITH SQUAMOUS-CELL CARCINOMA OF ORAL CAVITY AND
OROPHARYNX INCLUDED IN THIS STUDY
Site of SCC
Oral cavity
Tongue
Floor of mouth
Alveolus and gingiva
Hard palate
Buccal mucosa
Lip
Oropharynx
Tonsil
n
Stage
Grade
I
II
III
IV
I
II
III
22
6
12
3
5
5
6
1
1
1
1
3
5
2
3
0
3
1
7
0
3
0
0
3
4
3
5
2
1
0
11
3
6
2
2
4
9
2
3
1
2
1
2
1
3
0
1
0
6
0
1
3
2
2
3
1
(12%) died of the disease. Clinical data on recurrence and overall
survival were retrieved from clinical records. Serum samples were
stored at ⫺20°C until assayed.
Assays
Serum SCCAg was determined by the IMX method (Abbott,
Abbott Park, IL). The upper reference limit used for SCCAg in
serum was 2.5 µg/l.
Serum hCG␤ was determined by a time-resolved immunofluorometric assay (IFMA) based on 2 monoclonal antibodies to hCG␤
(Alfthan et al., 1988). The detection limit of the assay is 0.2 pmol/l
and the upper reference limit based on the 97.5 percentile of
apparently healthy controls is 2.0 pmol/l. The cross-reaction with
hCG, LH and LH␤ is ⱕ0.1% (Alfthan et al., 1992a).
Statistical analysis
Life-tables were calculated according to Kaplan-Meier. Patients
were divided into groups having a pre-operative tumor marker
value above or below the upper reference limit, and their recurrencefree survival was compared. The statistical significance of the
difference in recurrence-free survival between the groups was
calculated using the log-rank test. In addition, a Cox multivariate
survival analysis was performed, including the following covariates: age, gender, stage and grade of the tumor. The correlation
between the values of hCG␤ and SCCAg was calculated by the
Mann-Whitney U test. Recurrence-free survival and overall survival were defined by the time intervals between primary surgical
treatment and detection of recurrent disease, and death from SCC,
respectively.
TABLE II – UNIVARIATE ANALYSIS OF THE RELATIONSHIP BETWEEN
CLINICAL CHARACTERISTICS AND RECURRENCE-FREE SURVIVAL IN 59
PATIENTS WITH SQUAMOUS-CELL CARCINOMA OF ORAL CAVITY AND
OROPHARYNX*
Clinicopathological
variable
Pre-operative hCG␤
⬎2.0 pmol/l
ⱕ2.0 pmol/l
Pre-operative hCG␤
Continuous variable
Pre-operative SCCAg
⬎2.5 µg/l
ⱕ2.5 µg/l
Age, years
⬎64
ⱕ64
Gender
Female
Male
Grade
I
II
III
Stage
I
II
III
IV
Nodal state
N⫺
N⫹
Number of
Median recurrencepatients
free survival in months
8
51
4.4
15.1
59
␹2
p
6.83 0.009
6.71 0.01
12
47
7.5
14.2
0.27
NS
30
29
13.8
10.7
0.04
NS
27
32
15.2
11.6
0.63
NS
30
21
8
9.1
15.2
10.7
0.52
NS
13
15
14
17
15.3
14.2
6.7
5.9
7.7
0.006
37
22
14.2
6.7
5.05 0.025
*␹2
RESULTS
The median values for hCG␤ was 0.73 pmol/l and the range
0.10–12.2 pmol/l. Elevated pre-operative hCG␤ levels were observed in 8 out of 59 patients (14 %) and elevated SCCAg (median
1.6 µg/l, range 0.30–10.0 µg/l) in 12 (20%) of the patients (Table II)
(Figs. 1 and 2). There was no correlation between preoperative
hCG␤ and SCCAg levels (r ⫽ 0.09, p ⫽ 0.498).
Patients with pre-operatively elevated hCG␤ (⬎2.0 pmol/l) had
a shorter recurrence-free survival when compared with those with
normal hCG␤ levels (p ⫽ 0.009) (Fig.1). The risk ratio for
recurrence during follow-up for those with elevated hCG␤ was 3.6
(95% CI ⫽1.29–9.94). Of the patients with pre-operatively elevated serum hCG␤ 70% had recurrences within 12 months of
follow-up, while recurrences were detected in only 20% of those
with normal levels during the same period. Entering hCG␤ as a
continuous variable in a Cox regression analysis also showed a
significant association (p ⫽ 0.01) with recurrence-free survival.
There was no association between recurrence-free survival and
gender (p ⫽ 0.43), age (p ⫽ 0.84) or tumor grade (p ⫽ 0.77).
However, there was a significant association with stage of the
disease (p ⫽ 0.023, RR 3.03, 95% CI ⫽ 1.17–7.84). In a
multivariate survival analysis, hCG␤ and stage were independent
and corresponding p values were calculated by the log-rank test.
When the variable examined had 3 or more ordered categories, the
log-rank test for trend was used. NS, not significant.
prognostic factors (Table III). SCCAg showed no correlation with
recurrence-free survival (p ⫽ 0.605) (Table II) (Fig. 2).
Two of the patients with elevated hCG␤ (25%) and 5 of the
patients with normal hCG␤ (10%) died during follow-up (median
33 months). The corresponding figures for SCCAg were 2 patients
(17%), and 5 patients (11%), respectively. Because of the small
number of events, the difference in overall survival was not
determined.
DISCUSSION
Our results showed that patients with SCC of the oral cavity and
oropharynx with a pre-operatively elevated hCG␤ levels in serum
(⬎2.0 pmol/l) (14%) had shorter recurrence-free survival than
those with normal hCG␤ (p ⫽ 0.009). The risk for recurrent disease
in patients with pre-operatively elevated hCG␤ was 3.6-fold that of
patients with normal hCG␤.
HCG␤ IN SERUM AND ORAL CANCER PROGNOSIS
527
FIGURE 1 – Kaplan-Meier life-tables for patients with squamous-cell
carcinoma of the oral cavity and oropharynx (n ⫽ 59) grouped by
pre-operative serum hCG␤ value. The median recurrence-free survival
for 51 patients (dashed line) with an hCG␤ value ⬍2.0 pmol/l was 15
months, that for 8 patients (solid line) with an hCG␤ values ⱖ2.0
pmol/l, 4.4 months (p ⫽ 0.009).
FIGURE 2 – Kaplan-Meier life-tables for patients with squamous-cell
carcinoma of the oral cavity and oropharynx (n ⫽59) grouped by
pre-operative serum SCCAg value. The median recurrence-free survival for 47 patients (dashed line) with an SCCAg value ⬍2.5 pmol/l
was 14 months, that for 12 patients (solid line) with an SCCAg value
ⱖ2.5 pmol/l, 7.5 months (NS).
Several markers have been studied with a view to improving
evaluation of patients with SCCHN; they are: carcino-embryonic
antigen, CA 19–9, CA 125, alkaline phosphatase, CYFRA 21–1,
immune complexes, lipid-associated sialic acid, and SCCAg
(Doweck et al., 1995; Hanna et al., 1990; Rassekh et al., 1994).
However, although some of these are useful for monitoring some
patients, they do not provide prognostic information independent
of stage.
SCCAg, which was used as a reference marker in the present
study, was originally isolated and purified from a SCC of the
uterine cervix (Kato and Torigoe, 1977). Elevated serum levels of
SCCAg have been reported in patients with carcinoma of the
uterine cervix, esophagus and lung and are used for monitoring
these diseases (Kato and Torigoe, 1977). Earlier studies have
shown significant differences in postoperative SCCAg levels
between patients who remain disease-free and those who suffer
relapse (Eibling et al., 1989; Snyderman et al., 1995). However, in
accordance with the results of the present study, pre-operative
SCCAg-levels do not differentiate between the 2 groups (Eibling et
al., 1989; Snyderman et al., 1995).
HCG␤ has been shown to be expressed by a variety of
non-trophoblastic tumors (Iles et al., 1990). HCG␤ lacks gonadotropic activity (Marcillac et al., 1992), and little is known about its
biological function. However, has been shown to stimulate phospholipid methylation in Leydig cells (Ronco et al., 1993) and also the
growth of bladder cancer cell lines (Gillott et al., 1996). Thus,
hCG␤ may act as an autocrine growth factor for some tumor cells.
TABLE III – MULTIVARIATE ANALYSIS (COX PROPORTIONAL-HAZARDS
MODEL, BACKWARD STEPWISE, p TO REMOVE 0.05) OF RECURRENCE-FREE
SURVIVAL IN 59 PATIENTS WITH SQUAMOUS-CELL CARCINOMA OF ORAL
CAVITY AND OROPHARYNX*
Co-variate
p
95% CI
hCG␤
Stage
Grade
Gender
Age
0.039
0.044
NS
NS
NS
1.01–1.33
1.03–7.20
*hCG␤ was entered as ⬍2.0 pmol/l ⫽ 0, ⱖ2.0 pmol/l ⫽ 1, stage as
an ordinal variable (stage I–II ⫽ 0, stage III–IV ⫽ 1), grade as an
ordinal variable, high ⫽ 0, moderate ⫽ 1, low ⫽ 2, gender as male ⫽ 0,
female ⫽ 1, and age as ⬍64 years ⫽ 0, ⱖ64 years ⫽ 1. CI, confidence
interval; NS, not significant.
Such a function could explain why expression of hCG␤ is a sign of
poor prognosis.
Our results suggest that hCG␤ is an independent prognostic
marker in cancers of the oral cavity and oropharynx. Elevated
hCG␤ in serum identifies a high-risk group of patients. This finding
could be used to improve planning of surgical treatment and
subsequent follow-up in order to detect recurrent disease at an early
stage. We conclude that hCG␤ is a new potential marker in the
prognostic evaluation of patients with SCC of oral cavity and
oropharynx. Further studies to confirm these results should be
performed in larger patient groups and with longer follow-up.
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