ORIGINAL ARTICLE: CLINICAL

Clinical study on the serum carcinoembryonic antigen, CA 19-9,CA 50 and a-fetoprotein levels in patients withmyelodysplastic syndromes

MARIA DALAMAGA1, KONSTANTINOS KARMANIOLAS2, FANOURIOS KONTOS1,

ILIAS MIGDALIS2, & AMALIA DIONYSSIOU-ASTERIOU1

1Department of Clinical Biochemistry, Medical School, University of Athens, ‘Attikon’, General University Hospital,

Athens, and 2Department of Internal Medicine-Hematology Section, NIMTS General Hospital, Athens, Greece

(Received 24 January 2006; accepted 8 March 2006)

AbstractThe present study aimed to determine the serum carcinoembryonic antigen (CEA), CA 19-9, CA 50 and a-fetoprotein(a-FP) levels between patients with myelodysplastic syndromes (MDS) at diagnosis and controls to clarify their potentialclinical significance. A case – control investigation was conducted over a three year period, covering 95 MDS cases and95 age- and gender-matched controls. Mean serum CEA levels were significantly higher (P¼ 0.0002) in MDS patients atdiagnosis than in hospital controls. Adjusting for age, gender, tobacco consumption, serum CA 19-9, CA 50 and a-FP levels,there is statistically significant evidence that serum CEA values are associated with increased risk of MDS (odds ratio¼ 2.33,95% confidence interval¼ 1.56 – 3.49). Six patients with MDS developed malignancies 4 – 9 months after the diagnosis ofmyelodysplasia. Serum CEA could be used as marker together with other important diagnostic tools for evaluating anunderlying or developing malignancy in patients suffering from MDS.

Keywords: Myelodysplastic syndromes, tumor markers, carcinoembryonic antigen

Introduction

The myelodysplastic syndromes (MDS), also re-

ferred to as preleukemic syndromes [1] or

smoldering leukemia [2], are a heterogeneous group

of acquired clonal disorders of the stem cell,

characterized by ineffective hematopoiesis leading

to one or more peripheral blood cytopenias asso-

ciated typically with a normocellular or hypercellular

bone marrow [3 – 4]. These blood disorders, which

evolve progressively and often transform into acute

leukemia [5 – 6], generally arise de novo (idiopathic or

primary MDS), but may be seen after exposure

to radiotherapy or cytotoxic chemotherapy [7].

The French – American – British (FAB) Cooperative

Group proposed a classification scheme with five

morphologic subtypes of MDS, based upon bone

marrow and peripheral blood findings [8].

Malignant solid tumors as second neoplasms can

be seen with increased frequency in patients treated

for Hodgkin’s lymphoma as well as in patients with

chronic lymphocytic leukemia [9 – 10]. A relationship

between MDS and malignant solid tumors has also

been documented [11 – 12]. MDS patients present

a higher incidence of carcinomas than the general

population and MDS may be considered as a

paraneoplastic syndrome that could be present

before, simultaneously with, or after the diagnosis

of malignant solid tumors [13 – 14].

The present case – control investigation was con-

ducted at the large Veterans’ General Hospital

(NIMTS) in Athens, Greece. The aim of the study

was to determine the serum carcinoembryonic antigen

(CEA), CA 19-9, CA 50 and a-fetoprotein (a-FP)

levels between MDS patients at diagnosis and controls

to clarify their potential clinical significance. The

Correspondence: Maria Dalamaga, 19, 28th October, Agia Paraskevi, Post Code 15341 Athens, Greece. E-mail: madalamaga@med.uoa.gr

Leukemia & Lymphoma, September 2006; 47(9): 1782 – 1787

ISSN 1042-8194 print/ISSN 1029-2403 online � 2006 Informa UK Ltd.

DOI: 10.1080/10428190600688552

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evaluation of those markers could be clinically useful

for the following up of MDS patients in the potential

development of secondary malignancies.

Materials and methods

Both cases and controls were selected from patients

hospitalized at the NIMTS. The study covered 95

cases and 95 controls aged less than 87 years, who were

all of Greek nationality and permanent residents and

from the same study base. The veterans who partici-

pated in this study were mainly officers or non-

commissioned officers in Infantry (40%), Artillery

(35%), Armored Units (20%), Special Forces (3%)

and Transmission and Engineers’ Corps (2%). Med-

ical records were abstracted and interviews were

carried out to obtain information on demographic

characteristics, medical history and lifestyle variables.

Selection of cases

Eligible cases included newly diagnosed patients with

histologically confirmed primary MDS, aged less

than 87 years, consecutively admitted to the Internal

Medicine Department-Hematology Section of the

Veterans’ hospital between 1 February 2002 and

31 May 2005. All cases were classified according to

the FAB Cooperative Group scheme [8]. A total of

109 cases were identified and, of these, 95 cases

(54 males and 41 females), aged 44 – 87 years

(median age 74 years) were interviewed. The main

reason for non-participation was refusal on the part

of the subject or his/her relatives, but responders and

non-responders did not differ on demographic

variables, notably age, sex and year of diagnosis.

The predominant histological subtype of MDS in

this series was refractory anemia with or without

excess blasts in transformation (53 cases).

Selection of controls

Controls were patients, age less than 85 years,

admitted for non-neoplastic and non-infectious con-

ditions to the Orthopaedic and Otolaryngology

Department of the same hospital and matched to

cases on age (+5 years) and gender. No control

developed MDS. The main causes of admission to the

hospital in the control group were injuries and, in

particular, fractures not secondary to a disease,

scheduled hip or knee joint replacement due to

osteoarthritis, and vertigo. For every eligible case, an

attempt was made to randomly identify a control

admitted to the Veterans’ Hospital as closely as

possible in time to the corresponding case. A total of

118 potential controls were identified and, of these, 95

were interviewed. Among the latter, 54 were males

and 41 females, aged 47 – 85 years (median age 75

years). As for cases, the main reason for non-

participation was refusal on the part of the subject or

his/her relatives, but responders and non-responders

did not differ on demographic variables, notably age,

sex and year of diagnosis.

Data and specimen collection and laboratory analysis

A precoded questionnaire was administered to all

cases and controls by a trained interviewer, who also

reviewed the medical records. Sociodemographic and

medical variables and lifestyle characteristics, such as

tobacco smoking, were covered. Written informed

consent was obtained from all patients. Because most

patients were elderly, the questions were simple and

straightforward, without undue attention to details

that were difficult to ascertain and summarize. For

example, a 75-year-old smoker is likely to have gone

through periods of light or heavy smoking, of

unfiltered or filtered cigarettes of variable tar content.

This information, even when accurate, is difficult to

summarize and utilize. Eventually, three categories of

smoking status were examined: never smokers, ex-

smokers (that is those who quit smoking more than 3

years before the interview) and current smokers. The

main examinations performed at the time MDS was

diagnosed were bone marrow and trephine biopsy,

peripheral blood count, erythrocyte sedimentation

rate, biochemical laboratory evaluation, urine analysis

and chest X-ray. The chest X-ray did not reveal any

findings related to lung malignancy in both cases at

MDS diagnosis and controls. The blood specimens

used in this study were collected prior to the initiation

of chemotherapy or blood transfusions for the cases

and prior to any therapeutic approach, including

eventual surgery, for the control group. Peripheral

blood samples were centrifuged in the laboratory, and

serum was separated and stored at 7408C until

analysis. Serum CEA, a-FP, CA 19-9 and CA 50 levels

were radioimmunologically measured using reagent

kits obtained from CIS (Bio International, Gif-sur-

Yvette, France). The within-run and between-run

coefficients of variation of all the determinations were

3 – 5% and 5 – 7%, respectively (n¼ 15).

Statistical analysis

Statistical analysis of the data was performed with

SAS statistical software package, version 8 (SAS

Institute, Cary, NC, USA). Initially, data were

assessed by simple cross-tabulations and Student’s

t-test. The t-test was used to compare the serum

tumor markers values between cases and controls.

Subsequently, statistical analysis was under-

taken through multiple logistic regression [15 – 16].

Tumor markers in myelodysplasia 1783

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In the logistic regression model used, the response

variable was the probability of being from the MDS

‘case’ group and the predictor variables were the

covariates age and gender (matching factors), tobac-

co consumption and the serum tumor markers

(CEA, CA 19-9, CA 50 and a-FP) variables.

Variables that are significant predictors of MDS case

status are thus associated with MDS. Unconditional

logistic regression can be used without loss of validity

if the matching factors are accounted for [15 – 16].

We opted for unconditional rather than conditional

analysis to use the same approach when investigating

subtypes of MDS. In any case, the two approaches

generated similar results for the total series of MDS

cases.

Results

Table I depicts the distribution of the studied cases

of myelodysplastic syndromes and their matched

controls by sociodemographic factors (i.e. gender,

age and lifestyle variables, such as smoking

status) and the histological subtype of MDS amongst

cases according to the FAB classification scheme.

The mean+SD age of myelodysplastic patients

was 74.6+ 7.7 years (range 44 – 87 years). The

predominant histological subtype of MDS was

refractory anemia with approximately more than

one-third of all cases (35.8%) being diagnosed in

this category.

The mean+SD and range values for CEA, CA

19-9, CA-50 and a-FP in MDS patients and controls

are shown in Table II. Mean+SD CEA levels in 95

patients with MDS at diagnosis (3.18+ 2.05 ng/ml,

range 0.3 – 10.2 ng/ml) were significantly higher

(P¼ 0.0002) than in sera of 95 hospital controls

(2.15+ 1.6 ng/ml, range 0.8 – 8.9 ng/ml). Mean CA

19-9 levels in 95 patients with MDS at diagnosis

(13.59+ 4.14 U/ml, range 8.3 – 38.5 U/ml) were

not significantly higher (P¼ 0.43) than in sera of

95 hospital controls (13.09+ 4.52 U/ml, range

8.2 – 37.2 U/ml). Mean CA 50 levels in 95 patients

with MDS at diagnosis (12.99+ 3.21 U/ml, range

7.2 – 26.3 U/ml) were not significantly higher

(P¼ 0.13) than in sera of 95 hospital controls

(12.38+ 2.18 U/ml, range 8.2 – 19.6 U/ml). Finally,

mean a-FP levels in 95 patients with MDS at

diagnosis (1.73+ 1.02 ng/ml, range 0.6 – 6.8 ng/ml)

were not significantly higher (P¼ 0.38) than in sera

of 95 hospital controls (1.63+ 0.52 ng/ml, range

0.8 – 4.2 ng/ml). It is important to note that the

serum tumor markers values did not differ by age and

gender but differed by tobacco consumption.

Table III displays multiple logistic regression-

derived adjusted odds ratios (OR) and 95% con-

fidence intervals (CI) for a MDS in relation to age

and gender (matching factors), tobacco consumption

and serum tumor markers values. There is statisti-

cally significant evidence that serum CEA values are

associated with an increased risk of MDS. Adjusted

for age, gender, tobacco consumption, serum CA

19-9, CA 50 and a-FP levels, for two individuals

with serum CEA values that differ by one unit, the

individual with the larger value is approximately

Table I. Distribution of 95 cases of myelodysplastic syndromes and 95 age- and gender-matched controls by sociodemographic and lifestyle

variables, such as smoking status.

Cases Controls

Variable n (%) N (%)

Gender

Male 54 56.8 54 56.8

Female 41 43.2 41 43.2

Age (years)

565 9 9.5 10 10.5

65 – 69 13 13.7 16 16.8

70 – 74 26 27.4 21 22.1

75þ 47 49.4 48 50.6

Tobacco consumption

Never 49 51.6 64 67.4

Ex-smoker 23 24.2 12 12.6

Current smoker 23 24.2 19 20.0

FAB morphologic subtypes of MDS

Refractory anemia (RA) 34 35.8 – –

Refractory anemia with ringed sideroblasts (RARS) 12 12.6 – –

Refractory anemia with excess blasts (RAEB) 12 12.6 – –

Refractory anemia with excess blasts in transformation (RAEB-t) 19 20 – –

Chronic myelomonocytic leukemia (CMML) 16 16.8 – –

Unclassifiable MDS 2 2.2 – –

1784 M. Dalamaga et al.

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2.33-fold more likely to be a MDS case rather

than a control (OR¼ 2.33, 95% CI¼ 1.56 – 3.49).

By contrast, adjusted for other variables, serum CA

19-9-values might actually be lower in the MDS case

group (OR¼ 0.88, 95% CI¼ 0.79 – 0.99).

Six patients with MDS developed malignancies

4 – 9 months after the diagnosis of myelodysplasia.

Table IV depicts their clinical characteristics

and levels of serum tumor markers. The presented

serum tumor markers levels are those corresponding

to the time of first diagnosis of myelodysplasia. The

levels of serum CEA at diagnosis of myelodysplasia

seen in Table IV were above the reference range of

our laboratory (0 – 5 ng/ml) but not as elevated as

could be expected. It is important to emphasize that,

even if we exclude these six patients from the

statistical analysis, mean serum CEA levels in

89 patients with MDS at diagnosis were signifi-

cantly higher (P5 0.001) than in sera of 95 hospital

controls.

Finally, when patients with MDS were divided into

low risk MDS [refractory anemia (RA) and refractory

anemia with ring sideroblasts (RARS)] by virtue of

their infrequent transformation to acute myelogen-

ous leukemia [3] and high risk MDS [refractory

anemia with excess blasts (RAEB), refractory anemia

with excess blasts in transformation (RAEB-t),

chronic myelomonocytic leukemia (CMML) and

others], no statistically significant differences in the

serum CEA, CA 19-9, CA 50 and a-FP were noted.

Table II. Mean+SD and range values for tumor markers.

CEA CA 19-9 CA 50 a-FP

n (ng/ml) (U/ml) (U/ml) (ng/ml)

RR{ 0 – 5 537 525 515

MDS 95 3.18 (+2.05) 13.59 (+4.14) 12.99 (+3.21) 1.73 (+1.02)

Range: 0.3 – 10.2 Range: 8.3 – 38.5 Range: 7.2 – 26.3 Range: 0.6 – 6.8

Controls 95 2.15 (+1.6) 13.09 (+4.52) 12.38 (+2.18) 1.63 (+0.52)

Range: 0.8 – 8.9 Range: 8.2 – 37.2 Range: 8.2 – 19.6 Range: 0.8 – 4.2

P* 0.0002 0.43 0.13 0.38

*Using the t-test procedure, univariate analysis. {Reference ranges of our laboratory.

Table III. Multiple logistic regression analysis between MDS patients and hospital controls (as dependent variable) of age, gender, tobacco

consumption, CEA, CA 19-9, CA-50 and a-FP (as independent variables); regression coefficients (b), standard error of b (SEb) with

corresponding P-value, odds ratios (OR) and their 95% confidence intervals (95% CI).

Independent variable b SEb P OR 95% CI

Age (matched variable) 0.04 1.04 0.80 1.04 0.76 – 1.42

Gender (matched variable) 0.16 0.34 0.63 1.17 0.60 – 2.29

Tobacco consumption (never, ex-smoker, current smoker) 70.96 0.39 0.01 0.38 0.18 – 0.81

CEA 0.85 0.20 50.001 2.33 1.56 – 3.49

CA 19-9 70.12 0.06 0.03 0.88 0.79 – 0.99

CA-50 0.09 0.06 0.13 1.09 0.97 – 1.23

a-FP 0.22 0.21 0.29 1.25 0.83 – 1.89

Table IV. Clinical characteristics and levels of serum tumor markers in six patients with MDS who presented malignancies 4 – 9 months after

the diagnosis of myelodysplasia.

Age

(years) Gender MDS

Tumor

location Histopathology Stage

CEA

(ng/ml)

CA 19-9

(U/ml)

CA 50

(U/ml)

a-FP

(ng/ml)

69 Male CMML Lung Squamous cell carcinoma M1 8.5 17.2 10.2 2.1

72 Male CMLL Lung Squamous cell carcinoma T2N0M0 7.5 15.2 17.4 2.3

72 Male RAEB-t Colon Adenocarcinoma Dukes B 8.9 13.2 16.3 1.3

68 Female RAEB Colon Adenocarcinoma Dukes B 8.2 38.5 20.2 1.8

70 Female CMLL Breast Adenocarcinoma T1N1M0 6.2 21.1 12.3 1.5

71 Female Unclassifiable

MDS

Stomach Adenocarcinoma M1 6.5 13.2 13.2 1.6

Serum tumor markers levels are those corresponding to the time of first diagnosis of myelodysplasia.

Tumor markers in myelodysplasia 1785

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Discussion

The precise incidence of primary MDS has not been

accurately assessed by epidemiologic studies [8].

However, estimates indicate that the incidence varies

at approximately 25 per 100 000 per year after age

70 years [3 – 4]. MDS is uncommon before the age of

50 years with exception of treatment-related MDS

[3 – 4].

Weisdorf et al. [11] first reported the association

of malignant solid tumors as distinct from acute

leukemia in 17% of their MDS patients. This

association has also been observed in other studies

[12 – 14]. Moreover, a high incidence of lymphopro-

liferative and myeloproliferative disorders has been

recognized in patients with MDS [17 – 18]. In a

cohort study of MDS patients, Sans-Sabrafen et al.

[13] found that the incidence of carcinomas in MDS

patients was higher than in the general population.

Most patients in the previous study presented

cancers simultaneously with MDS or after the

diagnosis of MDS [13]. In the present study,

malignant solid tumors occurred 4 – 9 months after

diagnosis of myelodysplasia in six patients (lung

cancer in two patients, colon cancer in two, stomach

cancer in one and breast cancer in one; Table IV).

It would be interesting to follow-up our patients for a

diagnosis of malignant neoplasia and to determine

whether serum CEA could be an important prog-

nostic factor in MDS for survival and be used as a

marker, together with other important diagnostic

tools, for evaluating an underlying or developing

malignant solid tumor in MDS patients.

Serum CEA is clinically applied as a tumor marker

of colorectal, gastrointestinal, lung and breast carci-

noma and, in the healthy population, the upper limit

of CEA is greater for smokers than that of non-

smokers [19]. CA 19-9 is a tumor marker for both

colorectal and pancreatic carcinoma [19]. CA 50 is

used as a marker for pancreatic and digestive tract

carcinoma [19]. a-FP, which is synthesized in large

quantities during embryonic development by the

fetal yolk sac and liver, is a tumor marker for

hepatocellular and germ cell (nonseminoma) carci-

noma [19].

In the present study, we have found evidence that

serum CEA, but not CA 19-9, CA 50 and a-FP, tend

to increase in patients suffering from MDS at

diagnosis. The precise mechanism of CEA elevation

in MDS remains unclear and, to the best of our

knowledge, the clinical significance of CEA and

other tumor markers in MDS has not been described

[13]. The established hypotheses for the serum CEA

elevation were: (i) that MDS could be considered

as a paraneoplastic syndrome preceding the devel-

opment of solid malignant tumors [13]; (ii) that

patients with MDS have a higher incidence of

malignant neoplasia due mainly to the immunodefi-

ciency induced by MDS; and (iii) the inactivation

of tumor suppressor genes such as IRF-1 and p53,

the activation of oncogenes Ha-ras and c-fos and the

deregulation of the cell cycle inhibitor p21 in MDS

play a role in the pathogenesis of the disease and

could contribute to the development of malignant

tumors [20].

In conducting this case – control investigation con-

cerning serum tumor markers and MDS, the

important challenge stems from the low number of

cases, the rarity of this condition, and the dispersion

of patients for diagnosis and treatment among many

hospitals. Due to its convoluted history, for the last

century, Greece has always had a large army and

veterans and their families are concentrated for

medical care in the only Veterans’ hospital, allowing

the enrollment of a sufficient number of MDS cases

as well as controls from the same study base. This has

encouraged us to implement this study which, albeit

of modest size, was sufficiently large to generate

statistically documentable associations with serum

tumor markers.

In conclusion, the results of the present study

suggest that measurements of serum tumor markers,

especially CEA, revealed a potential clinical useful-

ness for monitoring MDS patients. Serum CEA

could be used as a marker together with other

important diagnostic tools for evaluating an under-

lying or developing malignancy in patients suffering

from MDS.

Acknowledgments

We are grateful to the Harvard Foundation which

provided support to Dr Maria Dalamaga.

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