We report a case of idiopathic interstitial pneumonia (IIP) with elevated serum levels of 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 at a 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

Burioka, Naoto

Hori, Shinji

Kawasaki, Yuji

Kometani, Yasushi

Nakada, Noriko

Sasaki, Takao

Suyama, Hisashi

Tatsukawa, Toshiyuki

Yonago Acta Medica

Tottori University Research Result Repository

147Idiopathic Interstitial Pneumonia with Increased Serum Levels of Cancer-Associated Antigens, CA19-9 and SLXNaoto Burioka, Hisashi Suyama, Toshiyuki Tatsukawa, Shinji Hori, YasushiKometani, Yuji Kawasaki, Noriko Nakada and Takao SasakiThird Department of Internal Medicine, Faculty of Medicine, Tottori University, Yonago 683,JapanWe 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 Japa-nese woman was admitted to our hospital with a fever, dry cough and dyspnea on exer-tion.  She had previously been admitted and had then been diagnosed as IIP.  Theserum 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 SLXwere changed during her clinical course.  These cancer-associated antigens were im-munohistochemically expressed on the hyperplastic bronchiolar epithelium, on the sur-face epithelium cells of microscopic honeycombing and on exudates in air space.  Repeat-ed damage to the lungs may have forced these antigens of the markers into the bloodcirculation, which may have resulted in the elevated serum levels of CA19-9 and SLXobserved in this patient.Key words:  CA19-9; cancer-associated antigen; idiopathic interstitial pneumonia; SLXAbbreviations:  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-iThe cancer-associated antigens, carbohydrateantigen 19-9 (CA19-9) (Koprowski et al., 1979)and sialyl Lewisx-i (SLX) (Fukushima et al.,1984), have been used as markers in the diagno-sis 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 fibro-sis (Frates et al., 1989; Wu et al., 1992), inter-stitial 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 treat-ed a female patient with idiopathic interstitialpneumonia (IIP) who had elevated serum levelsof CA19-9 and SLX.  We examined the serumlevels of these tumor markers and the immuno-histochemistry during her clinical course.Case ReportA 67-year-old Japanese woman was admitted toour hospital in August 1995 with a fever, drycough and dyspnea on exertion.  She had pre-viously been admitted because of an abnormal-ity observed on a chest radiograph in January1992. The diagnosis at that time was IIP.  Thepatient had not received corticosteroid therapy.Physical examination during present admis-sion revealed fine cracking lung sounds andcyanosis.  Her temperature was 38˚C.  The labo-ratory examination revealed the following:leukocyte count, 8400/mm3; a high level oflactic acid dehydrogenase (LDH, 307 IU/L,normal range, 100–225 IU/L); a high level of C-reactive 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)Yonago Acta medica 1997;40:147–151N. Burioka et al.148 CyclophosphamideMethylprednisolonePrednisolone50 mg(500 mg)60 mg60 mgtient was administered antibiotics at that time.Nevertheless, her symptoms and hypoxemia didnot improve.  Because of the worsened condi-tion of IIP, the patient was administered pred-nisolone (60 mg/day) intravenously in Septem-ber 1995.  An improvement in the PaO2 (53mmHg) of room air breathing was recognized.Reduction in the following parameters werenoted:  serum LDH (241 IU/L), ESR (28 mm/h), serum level of SLX (74 U/mL), and serumlevel of CA19-9 (21.4 U/mL) in October 1995.After an intravenous administration of methyl-prednisolone in November 1995, a respiratoryinfection was diagnosed.  Cough and dyspneaon exertion were worsened.  Oral cyclophos-phamide (50 mg/day) was added to the regimen.The patient’s condition deteriorated in February1996; serum levels of LDH (389 IU/L), SLX(110 U/mL), and CA19-9 (94.3 U/mL) wereagain elevated.  Mechanical ventilation wasinstituted, but the patient died in February 1996.There was a significant single linear correlationbetween the serum level of LDH and that ofCA19-9 during this patient’s clinical course(Fig. 2).  However, there was no significant cor-relation between the serum level of LDH andthat of SLX.≈and immunoglobulin M (320mg/dL) were all elevated.Tests for anti-nuclear anti-body and anti-DNA antibodywere negative.  A test for anti-body against hepatitis C virusor human T-cell lymphotropicvirus type I was negative.Mycobacterium in sputum cul-ture was negative.  Arterialblood gas analysis after breath-ing room air showed severehypoxemia (PaO2; 34 mmHg).The serum level of SLX, mea-sured by radioimmunoassay(RIA), was markedly elevated(120 U/mL; cut-off, < 38 U/mL) and the serum level ofCA19-9, measured by RIA,was slightly elevated (46 U/mL; cut-off, < 40 U/mL).  Thechest radiograph on admissionshowed reticular, small patches of infiltrate.Computed tomography of the chest demon-strated bilateral diffuse reticulo-nodular shadowsin the lung fields.  Gynecological examinationand computed tomographic images of the headand abdomen revealed no malignancy.The patient’s clinical course is summarizedin Fig. 1.  The IIP appeared to have been aggra-vated by infection in August 1995.  So, the pa-Fig. 2.  Single linear correlation between the serumlevel of LDH and that of CA19-9 during thispatient's clinical course.  A significant correlationwas observed (r = 0.891; P < 0.003).CA 19-9  ≈  ≈  ≈  ≈Fig. 1.  Clinical course.  , ESR; , LDH; , SLX;  , CA19-9. 100  90  80  70  60  50200 220 240 260 280 300 320 340 360 380 400LDH (IU/L)(U/mL)  40  30  20  10    0'92/1             '95/8      9       10      11      12     '96/1    2        3(year/month)ESR  LDH  SLX CA19-92001501005002001000400300200100500(mm/h)  (IU/L)  (U/mL) (U/mL) IIP with increase of tumor markers149Fig. 3.  Light microscopy showed a dilatation of the bron-chioles, a hyperplastic epithelium, severe fibrosis of thepulmonary parenchyma, anthracosis and infiltration ofinflammatory cells (hematoxylin and eosin stain, × 30).Fig. 4.  a, b: Transbronchial lung biopsy speci-men in January 1992. c, d: Necropsy specimen inFebruary 1996.a: Immunohistochemical staining with anti-CA19-9 monoclonal antibody showed negativereaction for CA19-9 (× 100).  b: Immunohisto-chemical staining with anti-SLX monoclonalantibody showed positive reaction for SLX on thebronchiolar surface epithelium (× 100).  Immuno-histochemical staining with anti-CA19-9 andanti-SLX monoclonal antibodies showed stronglypositive reactions for both CA19-9 (c) and SLX(d) on the hyperplastic bronchiolar epithelium, onthe flattened and cuboidal metaplastic epithelialcells of microscopic honeycoming and on exu-dates in the air spaces (× 100).Pathological findingsSpecimens of tissue from the respiratorytract were obtained at necropsy.  The lungexhibited a gross honeycomb appearance.Light microscopy showed dilatation of thebronchioles, a hyperplastic epithelium,severe fibrosis of the pulmonary parenchy-ma, anthracosis and infiltration of inflam-matory cells (Fig. 3).Immunohistochemical staining with anti-CA19-9 monoclonal antibody (1116-NS-19-9, TFB, Tokyo, Japan) showed negative re-action for CA19-9 on the lung specimen inJanuary 1992 (Fig. 4a).  Immunohisto-chemical staining with anti-SLX monoclonalantibody (Anti KM-93, Kyowa Medex,Tokyo) showed a positive reaction on thebronchiolar surface epithelium of the lungspecimen in January 1992 (Fig. 4b).  As forthe necropsy specimen in February 1996,immunohistochemical staining with anti-CA19-9 and anti-SLX monoclonal anti-bodies showed strongly positive reactionsfor both CA19-9 and SLX on the hyperplas-tic bronchiolar epithelium, on the flattenedand cuboidal metaplastic epithelial cells ofmicroscopic honeycoming and on exudates inthe air spaces (Figs. 4c and d).  No malignantfindings were recognized in the specimen ofthe patient’s lung.N. Burioka et al.150DiscussionWhen the patient had only a slightly dry coughwith slight abnormalities on the chest radio-graph in January 1992, the serum levels ofCA19-9 and SLX were within the normal range(Fig. 1).  To verify whether CA19-9 and SLXwere produced in the lungs, we examined im-munohistochemically their localization in thelungs of this patient by an enzyme-labeled anti-body method (Figs. 4a–d).  In her deterioratingcondition in August 1995, the serum levels ofCA19-9 and SLX were both elevated (Fig. 1).As IIP worsens, these cancer-associated antigensare increasingly expressed on the surface of thebronchiolar epithelium and on the flattened andcuboidal metaplastic epithelial cells ofmicroscopic 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 sialylatedglycoprotein tumor markers are immuno-histochemically expressed in the mucus cells ofbronchial hyperplastic glands and in the surfaceepithelium cells in patients with benign pul-monary 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), whichresulted in elevated serum levels of CA19-9 andSLX in this patient.  The serum level of SLXwas within the normal range despite expressionof SLX on the lung tissue in January 1992 (Fig.2b).  The destruction of the lung might be littleat that time.There was a significant correlation betweenthe serum level of LDH and that of CA19-9during this patient's clinical course. The serumlevel of LDH reportedly reflects damage to thelungs in interstitial pneumonia (De Remee,1968).  However, the serum level of LDH didnot parallel the serum level of CA19-9 duringDecember 1995 and January 1996. Althoughthe mechanism is unclear, the expression ofCA19-9 on the lung tissue might have beensuppressed in January 1996.  Treatment with acorticosteroid led to improvements in clinicalsymptoms and also led to reductions in serumlevels of CA19-9, SLX, ESR and LDH.  Thisfinding seems to indicate that the administra-tion 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 bene-ficial to distinguish some IIP patients who hadno 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.References 1 Atkinson BF, Ernst CS, Herlyn M, Steplewski Z,Sears HF, Koprowski H.  Gastrointestinal cancer-associated antigen in immunoperoxidase assay.Cancer Res 1982;42:4820–4823. 2 Bungo M, Yamaji Y, Futami H, Shiotani T, IrinoS, Okino T, et al.  A case of idiopathic interstitialpneumonia with marked increase of serum CA19-9.  Nippon Kyobu Shikkan Gakkai Zasshi 1988;26:185–189 (in Japanese). 3 Burioka N, Nogami S, Saito S, Ikeda T, HoshinoE, Matsumoto Y, et al.  A case of secondary infectedbronchiectasia accompanying uncommonlyelevated serum levels of CA19-9, SLX and SPan-1.  Nippon Kyobu Rinsho 1995;54:144–149 (inJapanese). 4 Chia D, Terasaki P, Suyama N, Galton J, HirotaM, Katz D.  Use of monoclonal antibodies tosialylated Lex and sialylated Lea for serologicaltest of cancer.  Cancer Res 1985;45:435–437. 5 De Remee RA.  Serum lactic dehydrogenaseactivity and diffuse interstitial pneumonitis.JAMA 1968;204:1193–1195. 6 Del Villano BC, Brennan S, Brock P.  Radio-immunometric assay for a monoclonal antibody-defined tumor marker, CA19-9.  Clin Chem 1983;29:549–552. IIP with increase of tumor markers151 7 Frates RC Jr, Fink RJ, Chernick MS, Brooks JO,Ginsburg V, Roberts DD. Serum mucin-associated antigen levels of cystic fibrosis pa-tients 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-associ-ated antigen.  Cancer Res 1984;44:5279–5285. 9 Koprowski H, Steplewski Z, Mitchell K, HerlynM, Herlyn D, Fuhrer P.  Colorectal carcinomaantigens 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 bronchialmucus 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, FukushimaK, Hiratani K, et al.  Two cases of interstitialpneumonitis with marked increase of tumor-associated carbohydrate antigens in serum.  NipponKyobu Shikkan Gakkai Zasshi 1991;29:611–617(in Japanese).(Received August 20, Accepted September 24, 1997)12 Mukae H, Hirota M, Kohno S, Komori K,Fukushima K, Hiratani K, et al.  Elevation oftumor-associated carbohydrate antigens in pa-tients with diffuse panbronchiolitis.  Am RevRespir 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 Lewisx-i(SLX) in diffuse panbronchiolitis.  NipponKyobu 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 sialylSSEA-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, NatoriY, Nakayama M, et al.  CA19-9 in patients withbenign pulmonary diseases.  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Idiopathic Interstitial Pneumonia with Increased Serum Levels of Cancer-Associated Antigens, CA19-9 and SLX

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Idiopathic Interstitial Pneumonia with Increased Serum Levels of Cancer-Associated Antigens, CA19-9 and SLX

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