CASE REPORT Loclized IgG4-relted Cholecystitis Mimicking Gllldder Cncer Tdhis Inoue 1, Fumihiro Okumur 1, Tkshi Mizushim 1, Hirotd Nishie 1, Hiroysu Iwski 1, Kiki Ane 1, Tknori Ozeki 1, Kent Kchi 1, Shigeki Fukusd 1, Yut Suzuki 1, Kzuko Wtne 2 nd Hitoshi Sno 1 Astrct We encountered cse of loclized IgG4-cholecystitis mimicking gllldder cncer with focl/segmentl type1 utoimmune pncretitis (AIP). In this cse, we were unle to exclude dignosis of gllldder cncer nd thus performed rdicl cholecystectomy. Type1 AIP is often ssocited with gllldder lesions, ccompnied y generlly diffuse, circumferentil thickening of the gllldder wll. Although loclized IgG4- relted cholecystitis is extremely rre, differentiting this condition from gllldder cncer is often very difficult. Key words: IgG4-relted cholecystitis, IgG4-relted disese, utoimmune pncretitis, gllldder neoplsms, denomyomtosis (Intern Med 54: 1869-1874, 2015) () Introduction In ptients with utoimmune pncretitis (AIP), vrious other orgns my e involved, with pthologicl findings similr to those oserved in the pncretic tissue. The condition IgG4-relted disese (IgG4-RD) is recently descried entity (1), nd IgG4-relted cholecystitis hs een noted s mnifesttion of IgG4-RD in the gllldder (2, 3). In generl, IgG4-relted cholecystitis is ssocited with IgG4- sclerosing cholngitis (IgG4-SC), which presents with diffuse, circumferentil thickening of the gllldder wll (3). Although this disese is extremely rre, cse of loclized IgG4-relted cholecystitis hs een reported (4). Differentiting loclized IgG4-relted cholecystitis from gllldder cncer is often very chllenging. We herein present cse of loclized IgG4-relted cholecystitis without ile duct lesions in which estlishing definitive dignosis sed on imging results ws very difficult. We elieve tht the present cse provides useful informtion for mnging ptients in whom IgG4-relted cholecystitis is suspected. In this report, we descrie the current cse with review of the literture. Cse Report A Jpnese womn in her sixties visited our hospitl for n evlution of gllldder tumor detected on dominl ultrsound (US) during medicl exmintion. She hd no symptoms nd hd neither relevnt medicl nor contriutory fmily history. The serum IgG4 level ws elevted t 813 mg/dl (norml rnge, 4.8 to 105 mg/dl) (Tle), while the levels of tumor mrkers, including crcinoemryonic ntigen (CEA) nd crohydrte ntigen 19-9 (CA19-9), were within the norml rnges. Adominl US reveled 15 10- mm solid tumor t the fundus of the gllldder (Fig. 1) nd 40-mm low-echoic tumor in the pncretic til (Fig. 1). In ddition, computed tomogrphy (CT) of the domen disclosed loclized, delyed-enhnced tumor in the gllldder (Fig. 2, ). The pncretic til tumor exhiited delyed enhncement; however, the extent of enhncement ws less thn tht oserved in the surrounding pncres (Fig. 2c, d). There were no normlities in ny other orgns, e.g., the ile duct, lymph nodes, slivry glnds or kidneys, nd mgnetic resonnce cholngiopncretogrphy Deprtment of Gstroenterology, Gifu Prefecturl Tjimi Hospitl, Jpn nd Deprtment of Pthology, Gifu Prefecturl Tjimi Hospitl, Jpn Received for puliction Octoer 27, 2014; Accepted for puliction Decemer 18, 2014 Correspondence to Dr. Tdhis Inoue, tinoue-tg@umin.c.jp 1869
Tle. Lortory Findings. WBC 4,200 / L Totl protein 7.7 g/dl CEA 1.75 ng/ml RBC 3.98 10 6 / L Alumin 4.2 g/dl CA19-9 4.54 U/mL Hemogloin 12.6 g/dl AST 10 IU/L Pltelets 18.0 10 4 / L ALT 15 IU/L IgG 1,725 mg/dl ALP 187 IU/L IgG4 813 mg/dl Totl iliruin 0.47 mg/dl BUN 14.8 mg/dl Cretinine 0.71 mg/dl N 141 meq/l K 4 meq/l Cl 106 meq/l CRP 0.17 mg/dl WBC: white lood cells, RBC: red lood cells, AST: sprtte minotrnsferse, ALT: lnine minotrnsferse, ALP: lkline phosphtse, BUN: lood urenitrogen, CRP: C-rective protein, CEA: crcinoemryonic ntigen, CA19-9: crohydrte ntigen 19-9, IgG: immunoglouling Figure 1. Adominl ultrsound (US) reveled solid tumor (rrows) t the fundus of the gllldder () nd low-echoic tumor (rrow) in the pncretic til (). showed no normlities in the ile duct (Fig. 3), lthough the min pncretic duct of the pncretic til ws not detected. Endoscopic ultrsonogrphy (EUS) reveled solid, loclized tumor in the fundus of the gllldder (Fig. 4) s well s hypoechoic nd heterogeneous tumor in the pncretic til with nrrowing of the min pncretic duct cused y the tumor (Fig. 4). No normlities of the ile duct, including thickening of the wll, were detected on EUS. Endoscopic retrogrde cholngiopncretogrphy reveled long segment of nrrowing long the min pncretic duct in the pncretic til (Fig. 5). Bsed on the these results, we suspected the pncretic til tumor to e focl/segmentl AIP. This led to the specultion tht the gllldder tumor ws lesion of IgG4- relted cholecystitis, lthough the possiility of gllldder polyps (e.g., hyperplstic polyps nd gllldder denom) ws lso considered during the differentil dignosis. However, we could not exclude dignosis of gllldder cncer ecuse the tumor ws loclized nd no thickening of the gllldder wll, except in the fundus, or ile duct lesions were detected, including signs of stenosis or dilttion. Therefore, rdicl cholecystectomy with simultneous spirtion iopsy of the pncretic til tumor ws performed. An exmintion of the surgiclly resected specimen demonstrted 15 10-mm tumor in the fundus of the gllldder (Fig. 6). The excised section contined yellow-white mss, nd multiple smll cystic lesions presenting s denomyomtosis in the tumor were oserved histologiclly. In ddition, histologicl exmintion reveled trnsmurl lymphoplsmcytic infiltrtion, storiform firosis, olitertive phleitis nd undnt IgG4-positive plsm cells (>10 cells per high-power field), with no evidence of mlignncy (Fig. 7). These findings were not oserved in res other thn the gllldder tumor nd regions in the vicinity. The iopsy specimen of the pncretic tumor showed lymphoplsmcytic sclerosing pncretitis without mlignncy, similr to the histologicl findings of the gllldder tumor. The finl pthologicl dignosis ws focl/segmentl type 1 AIP nd IgG4-relted cholecystitis. In the gllldder tumor, trnsmurl IgG4-relted cholecystitis ws interspersed with fundl-type denomyomtosis, nd the IgG4-relted chole- 1870
Intern Med 54: 1869-1874, 2015 c d Figure 2. Computed tomogrphy (CT) of the domen reveled 15 10-mm loclized, delyedenhnced tumor (rrow) in the gllldder (, ). A 40-mm pncretic til delyed-enhnced tumor (rrow) ws identified (c, d). Figure 3. Mgnetic resonnce cholngiopncretogrphy (MRCP) showed no normlities in the ile duct. The min pncretic duct of the pncretic til ws not detected. cystitis covered slightly wider re in the tumor thn the denomyomtosis. Orl prednisolone therpy ws initited fter the surgery, nd the pncretic til findings on CT improved. No signs of recurrence were oserved for three yers fter the initition of prednisolone. Discussion Type 1 AIP is chrcterized y enlrgement of the pn- cres, irregulr nrrowing of the pncretic duct nd n incresed serum IgG4 level (5). Type 1 AIP is systemic disese tht ffects multiple orgns, in ddition to the pncres, including the centrl nervous system, lcriml/slivry glnds, thyroid glnd, lungs, iliry duct, liver, gllldder, gstrointestinl trct, kidneys, prostte glnd, retroperitoneum, skin, rteries nd lymph nodes. Therefore, the term IgG4-RD ws recently coined, nd type 1 AIP is cknowledged to e pncretic lesion of IgG4-RD (1). Bile duct lesions, in prticulr, re frequently ssocited with type 1 AIP, which occurs longside IgG4-SC in pproximtely 60% to 80% of ptients (6, 7). Regrding gllldder lesions, Arhm et l. (2) reported tht 12 of 20 cses (60%) of AIP showed intense inflmmtory infiltrtion of the gllldder wll nd seven of 20 cses (35%) exhiited trnsmurl chronic cholecystitis. In ddition, Kmisw et l. (3) reported tht 10 of 19 cses (53%) of AIP demonstrted severe or moderte thickening of the gllldder wll, s oserved on rdiologicl exmintions, including US nd/or CT, while six of eight ptients (75%) with AIP undergoing surgery showed gllldder wll thickening on histologicl exmintions, including four ptients with firosis, IgG4positive plsm cells nd the trnsmurl inflmmtion of lymphocytes. IgG4-relted cholecystitis is minly ssocited with IgG4-SC (3, 8). In report of iliry lesions in 43 ptients with AIP (8), no gllldder wll thickening ws noted in nine ptients, with no ile duct lesions, wheres 1871
Figure 4. () Endoscopic ultrsonogrphy (EUS) reveled solid tumor (rrows) t the fundus of the gllldder. () EUS disclosed hypoechoic nd heterogeneous tumor in the pncretic til with nrrowing of the min pncretic duct (rrow) cused y the tumor. Figure 5. Endoscopic retrogrde cholngiopncretogrphy (ERCP) reveled long segment of nrrowing long the min pncretic duct (rrow) in the pncretic til. 69% (9/13) nd 19% (4/21) of the ptients with extensive ile duct involvement nd lower ile duct involvement only displyed gllldder wll thickening, respectively. In the ove-mentioned report of 19 ptients with AIP (3), ll ptients with gllldder wll thickening lso showed severe stenosis of the extrheptic ile duct. The present cse is extremely rre, s gllldder lesions were detected in the sence of ile duct lesions. Therefore, estlishing definitive dignosis ws chllenging in this cse. In IgG4-RD ptients, mlignnt tumors re often suspected, nd otining the differentil dignosis is often very difficult (9). Most ptients with IgG4-relted cholecystitis exhiit diffuse, circumferentil thickening of the gllldder wll ssocited with IgG4-SC or AIP. Therefore, confirming the dignosis is not difficult in typicl cses of IgG4-relted cholecystitis. However, in ptients with loclized gllldder lesions or inflmmtion extending to the surrounding tissue in the gllldder (mimicking the ppernce of mlignnt tumor), excluding the presence of gllldder cncer is chllenging. To dte, eight cses of IgG4-relted cholecystitis mimicking gllldder cncer hve een reported (4, 10-14). Most of the cses were not dignosed preopertively, nd Figure 6. The gross findings showed 15 10-mm tumor (rrow) in the fundus of the gllldder. The excised section contined yellow-white mss. surgicl tretment ws therefore performed. To the est of our knowledge, only one cse of loclized gllldder lesion similr to the present cse hs een reported (4). In tht report, the uthors speculted tht the loclized tumor hd developed s result of the comined effects of denomyomtosis nd IgG4-relted inflmmtion. In the present cse, IgG4-relted cholecystitis ssocited with fundl-type denomyomtosis ws oserved, similr to tht seen in the previously reported cse (4). The comined chnges induced y denomyomtosis nd IgG4-relted cholecystitis my promote the development of loclized tumors, thus requiring close dignostic ttention. In the present cse, the pncretic til tumor ws consid- 1872
c d Figure 7. Histopthologicl findings of the gllldder tumor. () Inflmmtory cell infiltrtion with firosis (Hemtoxylin nd Eosin (H&E) stining, 100). () The gllldder tumor exhiited storiform firosis (H&E stining, 200). (c) Aundnt IgG4-positive plsm cells were identified within the tumor (immunostining for IgG4, 400). (d) The gllldder tumor showed olitertive phleitis. (Elstic-Msson stin, 200). ered to e lesion of AIP. Therefore, dignostic steroid tril ws initilly considered. However, ccording to the interntionl consensus dignostic criteri for AIP, such trils should e initited only fter otining negtive findings on exmintions for cncer, including endoscopic US-guided fine-needle spirtion (15). It is more difficult to otin tissue for histologicl dignosis preopertively in gllldder lesions thn in pncretic lesions. The detection of AIP or IgG4-SC is n indiction of IgG4-relted cholecystitis; however, IgG4-relted cholecystitis my occur without ile duct lesions, s oserved in the present cse nd previously reported cse without AIP (12). Therefore, even if AIP or IgG4-SC is not oserved when dignosing gllldder lesions, the presence of IgG4-relted cholecystitis should e considered in the differentil dignosis. Hence, mesuring the serum IgG4 level is relevnt. The ccumultion of cses of IgG4-relted cholecystitis will help to clrify the typicl fetures of IgG4-relted cholecystitis on imging, therey ssisting in the differentil dignosis of gllldder cncer. As oserved in the present cse, the detection of delyedenhncement pttern on CT fcilittes the ility to otin definitive dignosis. However, if isolted or loclized gllldder lesions re detected nd the possiility of gllldder cncer cnnot e excluded, it is necessry to consider pproprite tretment strtegies, including surgicl resection. The uthors stte tht they hve no Conflict of Interest(COI). References 1. Umehr H, Okzki K, Mski Y, et l. A novel clinicl entity, IgG4-relted disese (IgG4RD): generl concept nd detils. Mod Rheumtol 22: 1-14, 2012. 2. Arhm SC, Cruz-Corre M, Argni P, Furth EE, Hrun RH, Boitnott JK. Lymphoplsmcytic chronic cholecystitis nd iliry trct disese in ptients with lymphoplsmcytic sclerosing pncretitis. Am J Surg Pthol 27: 441-451, 2003. 3. Kmisw T, Tu Y, Nkjim H, et l. Sclerosing cholecystitis ssocited with utoimmune pncretitis. World J Gstroenterol 12: 3736-3739, 2006. 4. Kwkmi H, Eto K, Kuwtni M, Ask M. Loclized lymphoplsmcytic sclerosing cholecystitis in ptient with utoimmune pncretitis. Intern Med 49: 2359-2360, 2010. 5. Finkelerg DL, Shni D, Deshpnde V, Brugge WR. Autoimmune pncretitis. N Engl J Med 355: 2670-2676, 2006. 6. Ohr H, Okzki K, Tsuouchi H, et l. Clinicl dignostic crite- 1873
ri of IgG4-relted sclerosing cholngitis 2012. J heptoiliry Pncret Sci 19: 536-542, 2012. 7. Okzki K, Yngw M, Mitsuym T, Uchid K. Recent dvnces in the concept nd pthogenesis of IgG4-relted disese in the hepto-ilio-pncretic system. Gut Liver 8: 462-470, 2014. 8. Kmisw T, Tkum K, Anjiki H, et l. Biliry lesions ssocited with utoimmune pncretitis. Heptogstroenterology 56: 1190-1193, 2009. 9. Erdogn D, Kloek JJ, ten Kte FJ, et l. Immunogloulin G4- relted sclerosing cholngitis in ptients resected for presumed mlignnt ile duct strictures. Br J Surg 95: 727-734, 2008. 10. Gums AA, Kim J, Kiehn E, Brink JA, Slem RR. Autoimmune pncretitis presenting s simultneous msses in the pncretic hed nd gllldder. JOP 6: 455-459, 2005. 11. Leise MD, Smyrk TC, Tkhshi N, Sweetser SR, Vege SS, Chri ST. IgG4-ssocited cholesystitis: nother clue in the dignosis of utoimmune pncretitis. Dig Dis Sci 56: 1290-1294, 2011. 12. Shin SW, Kim Y, Jeong WK, et l. Isolted IgG4-relted cholecystitis mimicking gllldder cncer: cse report. Clin Imging 37: 969-971, 2013. 13. Lee YS, Lee SH, Lee MG, et l. Immungloulin g4-relted disese mimicking unresectle gllldder cncer. Gut Liver 7: 616-620, 2013. 14. Feely MM, Gonzlo DH, Corer M, Hughes SJ, Trevino JG. IgG4-relted cholecystitis presenting s iliry mlignncy: report of three cses. J Gstrointest Surg 18: 1710-1715, 2014. 15. Shimosegw T, Chri ST, Frulloni L, et l. Interntionl consensus dignostic criteri for utoimmune pncretitis: guidelines of the Interntionl Assocition of Pncretology. Pncres 40: 352-358, 2011. 2015 The Jpnese Society of Internl Medicine http://www.nik.or.jp/imonline/index.html 1874