Clin J Gastroenterol (2012) 5:150–154 DOI 10.1007/s12328-012-0285-6

CASE REPORT

Elevation of carcinoembryonic antigen coinciding with disease activity of ulcerative colitis Sayaka Yamaguchi • Yoshiaki Takeuchi • Katsuhito Arai • Chitose Oishi • Tomoko Norose • Toshiko Yamochi-Onizuka Miki Kushima • Hidekazu Ota • Michio Imawari



Received: 6 July 2011 / Accepted: 16 January 2012 / Published online: 12 February 2012 Ó Springer 2012

Abstract We report on three cases of ulcerative colitis who presented with increased levels of serum carcinoembryonic antigen (CEA) during the active stage. All cases were pancolitis with a moderate to severe disease course. After remission induction with medical therapies, serum CEA levels decreased to the normal reference range. Immunohistochemical analyses demonstrated the existence of CEA not only along with the apical surface of the colonic epithelia but also at the cytosol of the inflamed epithelia where goblet cells were depleted during the active stage. We speculate that CEA was up-regulated by inflammatory response particularly in the process of epithelial regeneration. Keywords

Ulcerative colitis  Carcinoembryonic antigen

member of the immunoglobulin supergene family and functions as a homotypic inter-adhesion molecule in vitro [1]. Since it is abundantly expressed in the fetal gut, it has been thought to be an important molecule for tissue development and differentiation [2]. CEA was first discovered as an antigen of colon cancer cells [3], and has been used as a tumor marker of various organs. However, it is also known that CEA can increase in certain conditions such as benign diseases including liver cirrhosis, pancreatobiliary malignancies, and pulmonary disease and smoking [1]. We report on 3 cases of ulcerative colitis (UC) who presented with increased serum CEA concentrations. To explore possible mechanisms responsible for the increased CEA concentrations, we conducted immunohistochemical assessments.

Introduction Case report Carcinoma embryonic antigen (CEA) is a glycoprotein which is expressed at the surface of epithelial cells. It is a

S. Yamaguchi  Y. Takeuchi (&)  K. Arai  C. Oishi  M. Imawari Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawaku, Tokyo 142-8666, Japan e-mail: [email protected] T. Norose  M. Kushima Division of Diagnostic Pathology, Department of Pathology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawaku, Tokyo 142-8666, Japan T. Yamochi-Onizuka  H. Ota Department of Pathology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawaku, Tokyo 142-8666, Japan

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Case 1 A 44-year-old woman was admitted to our hospital because of bloody diarrhea ([10 times/day), fever, and abdominal pain. She was initially diagnosed as ulcerative proctitis in 2002, and since then she had been followed up at our institution. She voluntarily discontinued regular visits about 1 year before admission because of symptomatic resolution. She was not a smoker. At the time of admission she had malaise. On physical examination, her body temperature was 39°C. Blood pressure was 108/58 mmHg, and pulse was regular with a rate of 88 bpm. She was slightly anemic but not icteric. Her lungs were clear on auscultation and heart was normal. She complained of tenderness at the middle lower part of the abdomen although peritoneal signs were absent.

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Laboratory test demonstrated severe inflammatory reactions including white blood cell count (WBC) of 10,000 cells/mm3, erythrocyte sedimentation rate (ESR) of 70 mm/h and C-reactive protein (CRP) of 22 mg/dL. The serum hemoglobin was 9 g/dL and blood urea nitrogen, creatinine and blood glucose were 6, 0.55 and 101 mg/dL, respectively. Unexpectedly, CEA was increased to 17 ng/ dL (normal reference range \5 ng/dL). Colonoscopy revealed diffusely granular and edematous colonic mucosa with friability and shallow ulcerations extending from the rectum through to the caecum (Fig. 1). No neoplastic lesions were observed. Histological examination revealed infiltration of lymphocytes and plasma cells, and crypt abscess and depletion of goblet cells were noted, consistent with the active stage of UC. Immunohistochemistry demonstrated expression of CEA at the apical surface as well as the cytosol of the inflamed colonic epithelia (Fig. 2a).

Fig. 1 Colonoscopy revealed diffusely granular mucosa with erosions throughout the large intestine

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We diagnosed as UC flare-up with proximal extension, and corticosteroid was given in conjunction with leukocyte apheresis. She successfully achieved remission by the medical treatment and her serum CEA concentration decreased to 1.7 ng/dL. The work-up to examine causes for the increase of CEA including computed tomography (CT) scan and esophagogastroduodenoscopy were negative. The biopsy specimen obtained at the following colonoscopy showed CEA staining only at the apical surface (Fig. 2b). Case 2 A 67-year-old woman visited our hospital with a 2-month history of bloody diarrhea. She had 4–5 bowel movements per day but did not complain of abdominal pain. She had never smoked. At the time of presentation, she was not febrile. Blood pressure was 128/64 mmHg and pulse was 62 bpm with regular rhythm. She was neither anemic nor icteric. No chest abnormalities were found. Abdominal tenderness and peritoneal signs were absent. Laboratory tests showed WBC of 9,800 cells/mm3, blood urea nitrogen of 16.3 mg/dL, creatinine of 0.5 mg/ dL, blood glucose of 94 mg/dL and CRP of 3.3 mg/dL, respectively. The serum hemoglobin was 9 g/dL, and CEA was elevated at 17.2 ng/dL. Colonoscopy revealed diffusely granular and edematous mucosa with scattered erosions through the entire colon although rectal inflammation was modest (Fig. 3). Histological examination showed infiltration of lymphocytes with crypt abscess and distortion of the glands. CEA was modestly positive at the cytosol and the apical surface in the affected epithelia (Fig. 4a). A CT scan did not reveal any abnormalities other than the thickness of the large intestine. She was diagnosed as pancolitis (first attack). Although the severity was moderate, administration of oral

Fig. 2 a Immunohistochemistry revealed expression of CEA at the cytosol of the inflamed epithelia as well as the apical surface. b Immunohistochemistry after remission induction showed that expression of CEA was confined to the apical surface

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aminosalicylate (mesalamine) resulted in remission. The following colonoscopy showed completely healed mucosa with CEA being present only at the apical surface (Fig. 4b). The serum CEA normalized to 1.7 ng/dL after remission. Case 3 A 31-year-old woman was admitted to our hospital due to bloody diarrhea and abdominal pain. Diagnosis of UC was made in 2006, and she had experienced frequent flare-ups because of refractoriness to corcicosteroid. She had a history of oophorectomy and depression. She was not a smoker. On admission, she was ill-appearing and body temperture was 37°C. Blood pressure was 105/69 mmHg, and pulse was regular with a rate of 90 bpm. She was pale but not icteric. Her lung sounds were clear and no heart murmurs were audible. She had a soft abdomen but there was

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tenderness in the epigastrium and paraumbilical area without any peritoneal signs. Laboratory studies revealed anemia (hemoglobin 9.8 g/ dL), and WBC was 10,200 cells/mm3. Blood urea nitrogen, creatinine, blood glucose were 5.8, 0.59 and 102 mg/dL, respectively. Elevated CRP (17.34 mg/dL) and ESR (31 mm/h) were also noted. The serum CEA concentration was increased to 7.6 ng/dL. Colonoscopy revealed diffusely granular and edematous mucosa with multiple ulcerations extending up to the caecum without neoplastic lesions (Fig. 5). Findings of the histological examination were consistent with active UC—infiltration of lymphocytes, crypt abscess, and distortion of the glands. Immunohistochemistry showed a similar pattern to that of case 1 at the apical surface and the cytosol of the affected epithelia where goblet cells were depleted (Fig. 6a). A CT scan and esophagogastroduodenoscopy were negative except for an inflamed large intestine. Based on her history (steroid refractory), we administered cyclosporine for remission induction, which led to clinical remission. CEA was normalized (2.3 ng/mL) after induction of remission and cytosolic staining of CEA disappeared at the following colonoscopy (Fig. 6b). However, she presented again with flare-up and CEA was re-elevated at 13 ng/mL. She achieved remission by oral tacrolimus and her CEA again decreased to the normal reference range (2.4 ng/mL).

Discussion

Fig. 3 Diffusely granular and edematous mucosa with erosions were observed in the entire colon by colonoscopy

It has been reported that UC is a clinical condition that causes an increase of serum CEA concentrations. The 3 cases reported here presented increased CEA concentrations at their active stage. The lesions extended up to the caecum and the severity was moderate or severe. Our

Fig. 4 a CEA was weakly positive at the cytosol and the apical membrane. b Expression of CEA was observed only at the apical surface of the colonic mucosa

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findings were consistent with a report by Takimoto et al. that examined serum CEA concentrations in 154 UC patients; the incidence of CEA elevation was positively associated with more extensive and severe disease and immunohistochemical analysis revealed that frequency of CEA positivity was also associated with histological severity [4]. In order to examine the mechanisms of CEA elevations, we employed immunohistochemical analysis. As CEA is a membrane-bound glycoprotein, it was expressed at the apical surface of epithelia in healthy subjects (data not shown). Interestingly, we found that CEA was stained in the cytosol of the affected epithelia in the inflamed mucosa. In addition, we confirmed that the expression of CEA was observed only at the apical surface of the colonic epithelia after induction of remission in cases 1 and 3. Moreover,

Fig. 5 Diffusely granular mucosa with multiple ulcers were observed by colonoscopy

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clinical work-up did not show any other diseases or conditions leading to an increase in serum CEA concentrations. Taken together, it is apparent that increased serum CEA concentrations were due to up-regulation of expression of CEA in the colonic epithelia by active mucosal inflammation. Release of CEA into the bloodstream could lead to an increase of serum levels. The precise mechanisms of how inflammatory response leads to up-regulation of CEA are currently unknown. It has been demonstrated that expression of CEA is increased in colonic epithelial cells whose cell polarization was blocked [5]. Since polarization is a feature of cell differentiation, immature cells may have a greater ability to produce CEA. Therefore, it is conceivable that immature, regenerative epithelial cells promoted aberrant expression of CEA at the site of inflammation. Of particular note, cytosolic expression of CEA was found at the site where goblet cells were mostly depleted. It is known that the appearance of goblet cells is a feature of the healing phase of UC [6]. Our findings may indicate that CEA-positive epithelia were not completely repaired epithelia, but were in the process of regeneration. Interestingly, Fahlgren et al. [7] demonstrated that interferon-gamma tempered the expression of CEA family molecules in human colon cells. It is also possible that pro-inflammatory cytokines in affected mucosa could have promoted expression CEA. It may be interesting to see whether colonic inflammation by etiologies other than UC, such as infection and bowel ischemia, are capable of promoting CEA expression. We examined immunohistochemical analyses of CEA in patients with infectious colitis due to Campylobacter jejuni, which demonstrated its staining in a membranebound manner. To date, there has been no report demonstrating an increase of CEA during active colonic inflammation other than UC. Interestingly, Sminthson et al. [8] showed that expression of the antigen reactive with the

Fig. 6 a CEA was positive at the cytosol and the apical surface of the inflamed epithelia. b The cytosolic staining of CEA disappeared after remission

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monoclonal antibody which recognizes CEA was enhanced in active UC compared with quiescent UC and normal control. Thus, an increase of CEA expression by colonic inflammation could be characteristic of UC although more restrictive control study is needed. Takimoto et al. [4] reported that an increase of serum CEA levels was observed in 13% of patients with UC. The transcription of CEA is regulated by multiple nuclear transcriptional factors such as Sp1 and regulatory elements of its promoter region [9]. Hata et al. [10] found a functional single nucleotide polymorphism in an Sp1-binding site of the AGTRL1 gene which was associated with susceptibility to brain infarction. Meanwhile, it was shown that the transcription of CEA was correlated with DNA hypomethylation [11] and DNA methylation can be modulated by folate supplementation [12]. These genetic and/or environmental factors could contribute to interindividual differences in serum levels and tissue expression of CEA. In UC patients, the risk of colorectal cancer is higher in those with extensive disease of long duration and positive family history of colon cancer [13, 14]. As reported here, elevation of serum CEA concentrations can occur in active UC; therefore, interpretation of CEA in patients with UC must be cautious. Moreover, serum CEA concentrations do not necessarily correlate with tissue expression even in colorectal cancer [15]. Further studies may be needed about significance of determination of serum CEA concentrations in patients with UC. In conclusion, we experienced 3 cases of UC who presented with increased serum CEA concentrations, which may be attributable to enhanced expression of CEA in the epithelia of the inflamed mucosa. Conflict of interest The authors declare that they had no conflict of interest.

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Clin J Gastroenterol (2012) 5:150–154 2. Hammarstro¨m S, Olsen A, Teglund S. The nature and expression of the human CEA family. In: Stanners C, editor. Cell adhesion and communication mediated by the CEA family: basic and clinical perspectives. Amsterdam: Harwood Academic Publishers; 1997. p. 1–30. 3. Gold P, Freedman SO. Demonstration of tumor-specific antigens in human colonic carcinomata by immunological tolerance and absorption techniques. J Exp Med. 1965;121:439–62. 4. Takimoto A, Aida Y, Sugita A, Harada H, Yamamoto M, Ishiguro N, et al. Serum CEA value in patients with ulcerative colitis. Jpn J Gastroenterol Surg. 1992;25:508 (in Japanese). 5. Yan Z, Robinson-Saddler A, Winawer S, Friedman E. Colon carcinoma cells blocked in polarization exhibit increased expression of carcinoembryonic antigen. Cell Growth Differ. 1993;4:785–92. 6. Morson BC. Rectal biopsy in inflammatory bowel disease. N Engl J Med. 1972;287:1337–9. 7. Fahlgren A, Baranov V, Fra¨ngsmyr L, Zoubir F, Hammarstro¨m M-L, Hammarstro¨m S. Interferon-gamma tempers the expression of carcinoembryonic antigen family molecules in human colon cells: a possible role in innate mucosal defence. Scand J Immunol. 2003;58:628–41. 8. Smithson JE, Warren BF, Young S, Pigott R, Jewell DP. Heterogeneous expression of carcinoembryonic antigen in the normal colon and upregulation in active ulcerative colitis. J Pathol. 1996; 180:146–51. 9. Hauck W, Stanners CP. Transcriptional regulation of the carcinoembryonic antigen gene. Identification of regulatory elements and multiple nuclear factors. J Biol Chem. 1995;270:3602–10. 10. Hata J, Matsuda K, Ninomiya T, Yonemoto K, Matsushima T, Ohnishi Y, et al. Functional SNP in an Sp1-binding site of AGTRL1 gene is associated with susceptibility to brain infarction. Hum Mol Genet. 2007;16:630–9. 11. Tran R, Kashmiri SVS, Kantor J, Greiner JW, Pestka S, Shively JE, et al. Correlation of DNA hypomethylation with expression of carcinoembryonic antigen in human colon carcinoma cells. Cancer Res. 1988;48:5674–9. 12. Pufulete M, Emery PW, Sanders TAB. Folate, DNA methylation and colo-rectal cancer. Proc Nutr Soc. 2003;62:437–45. 13. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001;48: 526–35. 14. Askling J, Dickman PW, Karle´n P, Brostro¨m O, Lapidus A, Lo¨fberg R, et al. Family history as a risk factor for colon cancer in inflammatory bowel disease. Gastroenterology. 2001;120: 1356–62. 15. Guadagni F, Roselli M, Cosimelli M, Spila A, Cavaliere F, Arcuri R, et al. Quantitative analysis of CEA expression in colorectal adenocarcinoma and serum: lack of correlation. Int J Cancer. 1997;77:949–54.

Elevation of carcinoembryonic antigen coinciding with disease activity of ulcerative colitis.

We report on three cases of ulcerative colitis who presented with increased levels of serum carcinoembryonic antigen (CEA) during the active stage. Al...
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