Yonago Acta medica 1997;40:147–151

Idiopathic Interstitial Pneumonia with Increased Serum Levels of CancerAssociated Antigens, CA19-9 and SLX
Naoto Burioka, Hisashi Suyama, Toshiyuki Tatsukawa, Shinji Hori, Yasushi
Kometani, Yuji Kawasaki, Noriko Nakada and Takao Sasaki
Third Department of Internal Medicine, Faculty of Medicine, Tottori University, Yonago 683,
Japan
We report a case of idiopathic interstitial pneumonia (IIP) with elevated serum levelsof carbohydrate antigen 19-9 (CA19-9) and sialyl Lewisx-i (SLX). A 67-year-old Japanese woman was admitted to our hospital with a fever, dry cough and dyspnea on exertion. She had previously been admitted and had then been diagnosed as IIP. The
serum level of SLX, measured by radioimmunoassay (RIA), was markedly elevated(120 U/mL; cut-off, < 38 U/mL). The serum level of CA19-9, measured by RIA, was ata slightly high level (46 U/mL; cut-off, < 40 U/mL). The values of CA19-9 and SLX
were changed during her clinical course. These cancer-associated antigens were immunohistochemically expressed on the hyperplastic bronchiolar epithelium, on the surface epithelium cells of microscopic honeycombing and on exudates in air space. Repeated damage to the lungs may have forced these antigens of the markers into the blood
circulation, which may have resulted in the elevated serum levels of CA19-9 and SLX
observed in this patient.
Key words: CA19-9; cancer-associated antigen; idiopathic interstitial pneumonia; SLX

The cancer-associated antigens, carbohydrate
antigen 19-9 (CA19-9) (Koprowski et al., 1979)and sialyl Lewisx-i (SLX) (Fukushima et al.,1984), have been used as markers in the diagnosis of adenocarcinoma (Del Villano et al., 1983;
Chia et al., 1985). Serum CA19-9 and SLX are,however, frequently elevated in patients withbenign respiratory disease, such as cystic fibrosis (Frates et al., 1989; Wu et al., 1992), interstitial pneumonia (Bungo et al., 1988; Mukae etal., 1991), diffuse panbronchiolitis (DPB)(Noguchi et al., 1989; Mukae et al., 1993) andbronchiectasis (Burioka et al., 1995). We treated a female patient with idiopathic interstitial
pneumonia (IIP) who had elevated serum levelsof CA19-9 and SLX. We examined the serum
levels of these tumor markers and the immunohistochemistry during her clinical course.

Case Report
A 67-year-old Japanese woman was admitted toour hospital in August 1995 with a fever, dry
cough and dyspnea on exertion. She had previously been admitted because of an abnormality observed on a chest radiograph in January
1992. The diagnosis at that time was IIP. The
patient had not received corticosteroid therapy.
Physical examination during present admission revealed fine cracking lung sounds andcyanosis. Her temperature was 38˚C. The laboratory examination revealed the following:leukocyte count, 8400/mm 3; a high level oflactic acid dehydrogenase (LDH, 307 IU/L,
normal range, 100–225 IU/L); a high level of Creactive protein (CRP), 3.6 mg/dL; and a highlevel of erythrocyte sedimentation rate (ESR),
122 mm/h. Serum levels of immunoglobulin G(3477 mg/dL), immunoglobulin A (481 mg/dL)

Abbreviations: CA19-9, carbohydrate antigen 19-9; CRP, C-reactive protein; DBP, diffuse panbronchiolitis;
ESR, erythrocyte sedimentation rate; IIP, idiopathic interstitial pneumonia; LDH, lactic acid dehydrogenase;
PaO2, partial pressure of oxygen in arterial blood; RIA, radioimmunoassay; SLX, sialyl Lewisx-i

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N. Burioka et al.

CA 19-9≈≈≈≈≈

Cyclophosphamide
and immunoglobulin M (320
Methylprednisolone 50 mg
mg/dL) were all elevated.
(500 mg)
Tests for anti-nuclear anti- ESR LDH SLX CA19-9
body and anti-DNA antibody
60 mg
200 400 200 100
Prednisolone 60 mg(mm/h) (IU/L) (U/mL) (U/mL)
were negative. A test for antibody against hepatitis C virus
or human T-cell lymphotropic
150
virus type I was negative.
Mycobacterium in sputum culture was negative. Arterial
blood gas analysis after breath100 300 100
50
ing room air showed severe
hypoxemia (PaO2; 34 mmHg).
The serum level of SLX, mea50
sured by radioimmunoassay(RIA), was markedly elevated(120 U/mL; cut-off, < 38 U/
0 200
0
0
mL) and the serum level of
'92/1
'95/8
9
10
11
12 '96/1 2
3
CA19-9, measured by RIA,
(year/month)
was slightly elevated (46 U/
mL; cut-off, < 40 U/mL). The Fig. 1. Clinical course. , ESR; , LDH; , SLX; , CA19-9.
chest radiograph on admission
showed reticular, small patches of infiltrate. tient was administered antibiotics at that time.
Computed tomography of the chest demon- Nevertheless, her symptoms and hypoxemia did
strated bilateral diffuse reticulo-nodular shadows not improve. Because of the worsened condiin the lung fields. Gynecological examination tion of IIP, the patient was administered predand computed tomographic images of the head nisolone (60 mg/day) intravenously in Septemand abdomen revealed no malignancy.
ber 1995. An improvement in the PaO2 (53The patient’s clinical course is summarized mmHg) of room air breathing was recognized.
in Fig. 1. The IIP appeared to have been aggra- Reduction in the following parameters werevated by infection in August 1995. So, the pa- noted: serum LDH (241 IU/L), ESR (28 mm/h), serum level of SLX (74 U/mL), and serum(U/mL)
level of CA19-9 (21.4 U/mL) in October 1995.
100
After an intravenous administration of methyl90
prednisolone in November 1995, a respiratory80
infection was diagnosed. Cough and dyspnea
70
on exertion were worsened. Oral cyclophos60
phamide (50 mg/day) was added to the regimen.
50
The patient’s condition deteriorated in February40
1996; serum levels of LDH (389 IU/L), SLX
30(110 U/mL), and CA19-9 (94.3 U/mL) were
20
10
again elevated. Mechanical ventilation was0
instituted, but the patient died in February 1996.
200 220 240 260 280 300 320 340 360 380 400
There was a significant single linear correlation(IU/L)
LDH
between the serum level of LDH and that of
CA19-9 during this patient’s clinical course
Fig. 2. Single linear correlation between the serum(Fig. 2). However, there was no significant corlevel of LDH and that of CA19-9 during thisrelation between the serum level of LDH andpatient's clinical course. A significant correlation
was observed (r = 0.891; P < 0.003).
that of SLX.

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IIP with increase of tumor markers

Pathological findings
Specimens of tissue from the respiratory
tract were obtained at necropsy. The lungexhibited a gross honeycomb appearance.
Light microscopy showed dilatation of thebronchioles, a hyperplastic epithelium,
severe fibrosis of the pulmonary parenchyma, anthracosis and infiltration of inflammatory cells (Fig. 3).
Immunohistochemical staining with antiCA19-9 monoclonal antibody (1116-NS-199, TFB, Tokyo, Japan) showed negative reaction for CA19-9 on the lung specimen in
January 1992 (Fig. 4a). Immunohistochemical staining with anti-SLX monoclonal
antibody (Anti KM-93, Kyowa Medex,
Tokyo) showed a positive reaction on the
bronchiolar surface epithelium of the lungspecimen in January 1992 (Fig. 4b). As forthe necropsy specimen in February 1996,
immunohistochemical staining with antiCA19-9 and anti-SLX monoclonal antibodies showed strongly positive reactions
for both CA19-9 and SLX on the hyperplastic bronchiolar epithelium, on the flattened
and cuboidal metaplastic epithelial cells of
microscopic honeycoming and on exudates in
the air spaces (Figs. 4c and d). No malignant
findings were recognized in the specimen of
the patient’s lung.

Fig. 3. Light microscopy showed a dilatation of the bronchioles, a hyperplastic epithelium, severe fibrosis of thepulmonary parenchyma, anthracosis and infiltration of
inflammatory cells (hematoxylin and eosin stain, × 30).

Fig. 4. a, b: Transbronchial lung biopsy specimen in January 1992. c, d: Necropsy specimen in
February 1996.
a: Immunohistochemical staining with antiCA19-9 monoclonal antibody showed negative
reaction for CA19-9 (× 100). b: Immunohistochemical staining with anti-SLX monoclonal
antibody showed positive reaction for SLX on the
bronchiolar surface epithelium (× 100). Immunohistochemical staining with anti-CA19-9 andanti-SLX monoclonal antibodies showed strongly
positive reactions for both CA19-9 (c) and SLX(d) on the hyperplastic bronchiolar epithelium, on
the flattened and cuboidal metaplastic epithelial
cells of microscopic honeycoming and on exudates in the air spaces (× 100).

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N. Burioka et al.

Discussion
When the patient had only a slightly dry coughwith slight abnormalities on the chest radiograph in January 1992, the serum levels of
CA19-9 and SLX were within the normal range(Fig. 1). To verify whether CA19-9 and SLX
were produced in the lungs, we examined immunohistochemically their localization in thelungs of this patient by an enzyme-labeled antibody method (Figs. 4a–d). In her deteriorating
condition in August 1995, the serum levels of
CA19-9 and SLX were both elevated (Fig. 1).
As IIP worsens, these cancer-associated antigens
are increasingly expressed on the surface of thebronchiolar epithelium and on the flattened andcuboidal metaplastic epithelial cells of
microscopic honeycoming (Figs. 4c and d).
CA19-9 is synthesized, to some degree, by thenormal epithelial cells and respiratory glands ofthe airway (Atkinson et al., 1982; Matsuoka etal., 1990; Takayama et al., 1990), and SLX isalso synthesized, to some degree, by theepithelial cells of the normal airway (Shiota etal., 1989) in healthy subjects. These sialylated
glycoprotein tumor markers are immunohistochemically expressed in the mucus cells of
bronchial hyperplastic glands and in the surface
epithelium cells in patients with benign pulmonary diseases by inflammation (Noguchi etal., 1989; Mukae et al., 1991; Burioka et al.,1995). However, it has been unclear why thesecancer-associated antigens are expressed on thelung tissue of patients with IIP. Repeateddamage to the lungs may have forced theseantigens of the markers into the circulation(Noguchi et al., 1989; Mukae et al., 1991;
Mukae et al., 1993; Burioka et al., 1995), which
resulted in elevated serum levels of CA19-9 and
SLX in this patient. The serum level of SLX
was within the normal range despite expressionof SLX on the lung tissue in January 1992 (Fig.
2b). The destruction of the lung might be little
at that time.
There was a significant correlation between
the serum level of LDH and that of CA19-9
during this patient's clinical course. The serum

level of LDH reportedly reflects damage to thelungs in interstitial pneumonia (De Remee,1968). However, the serum level of LDH did
not parallel the serum level of CA19-9 during
December 1995 and January 1996. Although
the mechanism is unclear, the expression of
CA19-9 on the lung tissue might have been
suppressed in January 1996. Treatment with acorticosteroid led to improvements in clinicalsymptoms and also led to reductions in serum
levels of CA19-9, SLX, ESR and LDH. Thisfinding seems to indicate that the administration of a corticosteroid transiently inhibited theexacerbation of IIP. When a high serum levelof CA19-9 is recognized in IIP patients, thepossibility remains that an examination of thecorrelation between serum values of LDH andCA19-9 during the clinical course may be beneficial to distinguish some IIP patients who had
no malignant findings from the patients withadenocarcinoma.
Further study is needed to investigate whycancer-associated antigens are expressed in thelung tissue of the patient with IIP.

150

References
1 Atkinson BF, Ernst CS, Herlyn M, Steplewski Z,
Sears HF, Koprowski H. Gastrointestinal cancerassociated antigen in immunoperoxidase assay.
Cancer Res 1982;42:4820–4823.
2 Bungo M, Yamaji Y, Futami H, Shiotani T, Irino
S, Okino T, et al. A case of idiopathic interstitial
pneumonia with marked increase of serum CA199. Nippon Kyobu Shikkan Gakkai Zasshi 1988;
26:185–189 (in Japanese).
3 Burioka N, Nogami S, Saito S, Ikeda T, Hoshino
E, Matsumoto Y, et al. A case of secondary infected
bronchiectasia accompanying uncommonly
elevated serum levels of CA19-9, SLX and SPan1. Nippon Kyobu Rinsho 1995;54:144–149 (inJapanese).
4 Chia D, Terasaki P, Suyama N, Galton J, Hirota
M, Katz D. Use of monoclonal antibodies tosialylated Le x and sialylated Lea for serologicaltest of cancer. Cancer Res 1985;45:435–437.
5 De Remee RA. Serum lactic dehydrogenase
activity and diffuse interstitial pneumonitis.
JAMA 1968;204:1193–1195.
6 Del Villano BC, Brennan S, Brock P. Radioimmunometric assay for a monoclonal antibodydefined tumor marker, CA19-9. Clin Chem 1983;
29:549–552.

IIP with increase of tumor markers

7 Frates RC Jr, Fink RJ, Chernick MS, Brooks JO,
Ginsburg V, Roberts DD. Serum mucinassociated antigen levels of cystic fibrosis patients are related to their ages and clinical statuses.
Pediatr Res 1989;25:49–54.
8 Fukushima K, Hirota M, Terasaki P, Terasaki P,
Wakisaska A, Tagashi H, et al. Characterizationof sialosylated Lewis X as a new tumor-associated antigen. Cancer Res 1984;44:5279–5285.
9 Koprowski H, Steplewski Z, Mitchell K, Herlyn
M, Herlyn D, Fuhrer P. Colorectal carcinoma
antigens detected by hybridoma antibodies.
Somatic Cell Genet 1979;5:957–972.
10 Matsuoka Y, Endo K, Kawamura Y, Yoshida T,
Saga T, Watanabe Y, et al. Normal bronchial
mucus contains high levels of cancer-associatedantigens, CA125, CA19-9, and carcinoembryonicantigen. Cancer 1990;65:506–510.
11 Mukae H, Sakito O, Oda H, Senju R, Fukushima
K, Hiratani K, et al. Two cases of interstitial
pneumonitis with marked increase of tumorassociated carbohydrate antigens in serum. Nippon
Kyobu Shikkan Gakkai Zasshi 1991;29:611–617(in Japanese).

12 Mukae H, Hirota M, Kohno S, Komori K,
Fukushima K, Hiratani K, et al. Elevation oftumor-associated carbohydrate antigens in patients with diffuse panbronchiolitis. Am Rev
Respir Dis 1993;148:744–751.
13 Noguchi M, Nakatani T, Chonabayashi N,
Nakamori Y, Nakata K, Matsushita H, et al.
Clinical evaluation of serum sialyl Lewis x-i(SLX) in diffuse panbronchiolitis. Nippon
Kyobu Shikkan Gakkai Zasshi 1989;27:317–325(in Japanese).
14 Shiota T, Matsubara Y, Ikeda S, Ishida H,
Katsura A, Hanawa T, et al. Evaluation of sialyl
SSEA-1 antigen in patients with lung cancer.
Nippon Gan Chiryo Gakkaishi 1989;24:1067–
1073 (in Japanese).
15 Takayama S, Kataoka N, Usui Y, Inase N, Natori
Y, Nakayama M, et al. CA19-9 in patients withbenign pulmonary diseases. Nippon Kyobu
Shikkan Gakkai Zasshi 1990;28:1326–1331 (inJapanese).
16 Wu JT, Olson J, Walker K. Tumor markers
CA19-9 and CA195 are also useful as markers for
cystic fibrosis. J Clin Lab Anal 1992;6:151–161.

(Received August 20, Accepted September 24, 1997)

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