CASE REPORT. Abstract. Introduction. Case Reports
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1 CASE REPORT Ulertive Colitis-ssoited Cner/Dysplsi Deteted Using Surveillne Colonosopy Performed in the Clinil Remission Phse: A Report of Five Cses Ruiko Murok 1, Keiihi Toming 1, Xuin Si 1, Kzuhiro Tkenk 1, Tkeshi Sugy 1, Mskzu Nkno 1, Noto Yoshitke 1, Storu Ymguhi 2, Hitoshi Ngt 3, Hidetsugu Ymgishi 4, Hiroyuki Mitomi 5 nd Hideyuki Hirishi 1 Astrt We herein report five ses of ulertive olitis-ssoited ner/dysplsi. Although linil remission hd een hieved in ll ptients, muosl inflmmtion hd een resolved in only one ptient. Thus, in order to prevent ner from developing, pproprite medil therpy iming not only to relieve the linil symptoms, ut lso to suppress hroni inflmmtion ppers to e neessry. Moreover, ner ourred s erly s 4 yers fter the dignosis in one ptient. In ptients without omplete resolution of muosl inflmmtion, reful surveillne olonosopy should e initited in the erly phse. Key words: ulertive olitis-ssoited ner, dysplsi, linil remission, muosl inflmmtion, surveillne olonosopy (Intern Med 55: , 2016) () Introdution Ptients with ulertive olitis my develop ulertive olitis-ssoited ner/dysplsi (UCACD). The linil risk ftors for developing UCACD inlude the durtion of disese, extent of disese, fmily history of oloretl ner, onurrent presene of primry slerosing holngitis, onset t n erly ge, presene of kwsh ileitis, nd severity of histologil inflmmtion (1-5). Prtiulrly, persistent muosl inflmmtion is n importnt risk ftor for developing ner, nd it is suggested tht omplete resolution of muosl inflmmtion my redue the inidene of UCACD (6-8). On the other hnd, the reported signifint inhiitory ftors for developing ner inlude prophylti oletomy performed t the time of deteting dysplsi, regulr hospitl visits, endosopi surveillne, nd drug dherene (9). Cse Reports We herein report five ses of UCACD tht were deteted using surveillne olonoosopy fter linil remission ws hieved (Tle 1, 2). Tle 1 shows the overll ptient hrteristis, nd Tle 2 shows the liniopthologil fetures of eh se. In this rtile, linil remission ws defined s Rhmilewitz linil tivity index (CAI) of 4 points or less (10). Cse 1 A 21-yer-old mn developed extensive, relpsingremitting ulertive olitis t 15 yers of ge. He hd een treted with 5-minosliyli id (5-ASA). In the erly period fter onset, it ws diffiult to mintin remission, nd he ws hospitlized twie for tretment. Beuse he ws re- Deprtment of Gstroenterology, Dokkyo Medil University, Jpn, First Deprtment of Surgery, Dokkyo Medil University, Jpn, Seond Deprtment of Surgery, Dokkyo Medil University, Jpn, Deprtment of Antomi nd Dignosti Pthology, Dokkyo Medil University, Jpn nd Deprtment of Surgil nd Moleulr Pthology, Dokkyo Medil University, Jpn Reeived for pulition My 7, 2015; Aepted for pulition July 26, 2015 Correspondene to Dr. Keiihi Toming, toming@dokkyomed..jp 911
2 Tle 1. Demogrphi nd Clinil Chrteristi of Ptients with Ulertive Colitis. Chrteristis All ptients n = 5 Sex (men/women), n (%) 3 (60) /2 (40) Age (yers) 39.2 (15-67) Disese durtion (yers) Extent of disese Extensive olitis, n (%) 1 (20) Left-side type, n (%) 4 (80) Clinil ourse Chroni-ontinuous, n (%) 0 (0) Relpsing-remitting, n (%) 5 (100) Dysplsi, n (%) 1 (20) Erly ner, n (%) 2 (40) Advned ner, n (%) 2 (40) P53 Positive, n (%) 4 (80) Negtive, n (%) 1 (20) Fmily history of oloretl ner, n (%) 0 (0) Conurrent primry slerosing holngitis, n (%) 0 (0) Presene of prolonged inflmmtion, n (%) 5 (100) Muosl inflmmtion Present, n (%) 4 (80) Asent, n (%) 1 (20) Tle 2. Cliniopthologil Fetures of Eh Cse. Cse Age of onset (y) Age of ner development (y) Disese durtion efore ner development (y) ASA dose (mg/dy) 4,000 3,600 4,000 4,000 4,000 Durtion of 5-ASA dministrtion (y) Totl steroid dose (mg) 4,284 8, ,375 Durtion of steroid dministrtion 1 yer 9 months 2 yers 5 months 5 months 3 yers 9 months Totl immunomodultory drug dose (mg) 88,800 15,000 46, ,500 Durtion of immunomodultory drug dministrtion 5 yers 2 months 10 months 4 yers 4 months 8 yers 5 months Preopertive histologil dignosis high grde dysplsi well-differentited well-differentited poorly differentited high grde dysplsi Postopertive histologil dignosis well-differentited intrmuosl signet-ring ell rinom well-differentited Postopertive follow-up period (s of June 2015) live for 2 yers 4 months live for 2 yers live for 2 yers live for 1 yer 3 months live for 1 yer sistnt to steroids, immunomodultory drugs were introdued, whih suffiiently improved his onditions to llow outptient tretment. Two yers lter, lthough linil remission (3 points on the CAI) ws hieved, olonosopy (CS) reveled tive muosl inflmmtion with n invisile vsulr pttern, ppering red in the left side of the olon. In CS performed 3 yers lter, lthough the findings of muosl inflmmtion were omprle to those of the previous CS, protruded lesion ws deteted in the retum (Fig. 1). High-grde dysplsi ws pthologilly dignosed, nd surgery ws performed. The surgil findings reveled well-differentited mesuring m tht prtilly infiltrted the musulris muose in the retum. Beuse of the oexistene of high-grde dysplsi round the nd diffuse positivity for P53 fter immunostining of the lesion (Fig. 1, ), UCACD ws dignosed. 912
3 Figure 1. : A protruding lesion ws oserved in the retum. : A well-differentited prtilly infiltrted the musulris muose, nd high-grde dysplsi oexisted round the. : Diffuse positivity for P53 ws oserved in the lesion. Cse 2 A 71-yer-old mn developed extensive, relpsingremitting ulertive olitis t 67 yers of ge. After remission, indution therpy with prednisolone (PSL) ws initited, nd linil remission (1 point on the CAI) hd een mintined y 5-ASA lone. However, CS performed 4 yers lter reveled exerted muosl inflmmtion nd reddish protruded lesion in the distl sigmoid olon Figure 2. : A reddish protruding lesion ws oserved in the sigmoid olon. : Infiltrtion of hroni inflmmtory ells predominntly onsisting of diffuse lymphoytes nd plsm ells ws oserved in the muosl lyer nd musulris propri extending from the retum to the sigmoid olon nd ompnied y mild rypt sess. High-grde dysplsi round the intrmuosl ws oserved in the sigmoid olon. : The lesion ws negtive for P53 on immunostining. (Fig. 2). Well-differentited ws pthologilly dignosed, nd surgery ws performed. The surgil findings reveled high-grde dysplsi/intrmuosl with mjor xis of 0.8 m tht ws diffiult to identify mrosopilly in the sigmoid olon. The histopthologil fetures of this se inluded the prolifertive 913
4 Cse 3 A 39-yer-old womn who developed extensive, relpsing-remitting ulertive olitis t 24 yers of ge ws treted with 5-ASA. Although inptient tretment hd osionlly een required, linil remission (1 point on the CAI) ws hieved when she ws 31 yers of ge. However, CS performed 5 yers lter reveled tive muosl inflmmtion with invisile vsulr pttern, ppering red in the entire olon. Furthermore, during CS performed 3 yers lter, lthough the findings of muosl inflmmtion were omprle to those otined on the previous CS, flt protruded lesion with reltively well-defined mrgin ws deteted in the sending olon (Fig. 3). A well-differentited ws pthologilly dignosed, nd surgery ws performed. The surgil findings reveled n mesuring 0.3 m in the sending olon. Beuse the ws surrounded y low- to high-grde dysplsi nd showed diffuse positivity for P53 on immunostining (Fig. 3, ), UCACD ws dignosed. Cse 4 A 67-yer-old mn hd developed left-sided, relpsingremitting ulertive olitis t 44 yers of ge, whih eme highly tive soon fter onset, nd hroni inflmmtion hd persisted for mny yers. At 63 yers of ge, fter remission ws indued y PSL nd grnuloyte-monoyte dsorption pheresis, remission mintenne therpy ws initited with 5-ASA plus immunomodultory drugs, resulting in linil remission (1 point on the CAI). Complete resolution of muosl inflmmtion ws oserved t 64 yers of ge, nd the findings of CS performed 2 yers lter were omprle to those of the previous CS. However, CS performed 3 yers lter reveled hemorrhgi tumorous lesion in the retum, mesuring pproximtely 3.0 m. The lesion ws pthologilly dignosed s poorly-differentited, nd surgery ws performed (Fig. 4). Beuse the tumor ws signet-ring ell rinom extending eyond the musulris propri nd showed diffuse positivity for P53 on immunostining (Fig. 4, ), UCACD ws dignosed. Figure 3. : A flt, protruding lesion with reltively welldefined mrgin ws oserved in the sending olon. : Adenorinom ws oserved in the sending olon, nd low- to high-grde dysplsi ws oserved round the. : The lesion ws positive for P53 on immunostining. zone loted in the middle to deep muosl lyer, tumor existing in the dutl struture, nd high-grde dysplsi existing round the tumor. Immunostining for P53 ws negtive (Fig. 2, ). It hs een previously reported tht even in UCACD, pproximtely 40% of ses re negtive for immunostining for P53 (11, 12). Therefore, UCACD ws omprehensively dignosed. Cse 5 A 57-yer-old womn developed extensive, relpsingremitting ulertive olitis t 46 yers of ge. Clinil remission (1 point on the CAI) hd een hieved y tretment with 5-ASA plus zthioprine. At 55 yers of ge, CS reveled tive muosl inflmmtion with invisile vsulr pttern, ppering red. At 57 yers of ge, lthough CS reveled tht the extent of muosl inflmmtion ws omprle to tht shown on the previous CS, protruded lesion with n irregulr surfe ws deteted in the desending olon. The lesion ws pthologilly dignosed s high-grde dysplsi, nd surgery ws performed (Fig. 5). The surgil findings reveled protruded lesion mesuring m in the sigmoid olon, whih ws well-differentited infiltrting the superfiil lyer of the musulris 914
5 Intern Med 55: , 2016 Figure 4. : A hemorrhgi tumor lesion mesuring pproximtely 3m ws oserved in the retum. : The tumor ws signet-ring ell rinom extending eyond the musulris propri. Muosl inflmmtion in the re other thn the tumor lesion ws mild. : The lesion ws positive for P53 on immunostining. Figure 5. : A protruding lesion ws oserved in the sigmoid olon. : The tumor in the sigmoid olon ws welldifferentited tht infiltrted the superfiil lyer of the musulris propri. : Immunostining for P53 showed diffuse positivity in the lesion. propri. Moreover, nother protruded lesion mesuring m ws deteted in the desending olon tht hd infiltrted the sumuos. Due to the presene of multiple tumors, the existene of high-grde dysplsi round the tumors, nd diffuse positivity for P53 on immunostining of the lesions (Fig. 5, ), UCACD ws dignosed. Disussion Ptients with long-stnding ulertive olitis re t high risk of developing ner. Aording to met-nlysis performed y Eden et l., the umultive inidene of ner is reported to e 1.6% t 10 yers fter the onset of ulertive olitis, 8.3% t 20 yers, nd 18.4% t 30 yers (13). Aording to the CS findings, signifint risk ftors for de- 915
6 veloping UCACD inlude the severity of inflmmtion, enem findings of led-pipe olon, inflmmtory polyposis, striture, nd n intestine showing ontrtion (14). All these ftors indite period of severe inflmmtion or prolonged durtion of inflmmtion. Even if the disese tivity is linilly low, ptients whose disese hs remined endosopilly tive for long period re ssumed to e t high risk of developing ner euse of n inresed umultive durtion of inflmmtion. On the other hnd, omplete endosopi resolution of muosl inflmmtion is onsidered to e signifint ftor for lowering the risk (15). Although linil remission ws hieved in ll five ptients enountered, omplete resolution of muosl inflmmtion ws not hieved in four ptients, exluding one (Cse 4). Rosenerg et l. reported tht omplete resolution of endosopi muosl inflmmtion ws hieved in only 55% of 149 ptients with ulertive olitis in whom linil remission ws onfirmed (16). In our five ptients, euse ll hd prolonged inflmmtion during the linil follow-up nd did not show endosopi relief of muosl inflmmtion, it is ssumed tht the risk of ner remined high. Tretment with 5-ASA hs een reported to redue the inidene of oloretl ner/epithelil dysplsi y 49% (17), whih suggests the usefulness of 5-ASA for the tretment for UCACD. However, ner ourred in our five ptients, even though ll ptients reeived n orl dministrtion of 5-ASA. Possile resons for ner development inlude prolonged durtion of inflmmtion nd lk of resolution of muosl inflmmtion. In the Europen Crohn s nd Colitis Orgniztion (ECCO) Workshop in 2011, it ws reported tht omplete resolution of muosl inflmmtion might ontriute to deresed inidene of UCACD (18). Mny Europen nd Amerin guidelines reommend performing the first sreening endosopy in the eighth to tenth yer fter disese onset (19-21). Menwhile, there is report tht, euse pproximtely 20% of the ses of UCACD our within 8 yers fter the onset of inflmmtory owel disese, the detetion of ner ws delyed in pproximtely 20% of ses when surveillne ws strted in the periods reommended y the Europen nd Amerin guidelines (22). Thus, in the 2012 version of the ECCO guidelines, the reommended period for inititing surveillne ws set erlier, to 6 to 8 yers fter onset (23). While we hve lso set our guidelines for surveillne olonosopy ording to these guidelines, our series inluded ptient who developed ner fter only 4 yers. Thus, in ptients without omplete resolution of muosl inflmmtion, reful SC must e initited in the erly phse. At present, with men follow-up of 1.7 yers (rnge, 1 to 2.4 yers) fter surgery, our five ptients re live without either reurrene or metstsis. We herein reported five ses of UCACD. The umultive effet of tive inflmmtion in ulertive olitis ppers to e n importnt ftor losely ssoited with tumorigenesis. In order to prevent ner from developing, pproprite medil therpy iming not only for relief of the linil symptoms, ut lso suppression of hroni inflmmtion nd omplete resolution of muosl inflmmtion ppers to e neessry. The uthors stte tht they hve no Conflit of Interest (COI). Referenes 1. Ekom A, Helmik C, Zk M, Admi HO. Ulertive olitis nd oloretl ner. A popultion-sed study. N Engl J Med 323: , Itzkowitz SH, Hrpz N. Dignosis nd mngement of dysplsi in ptients with inflmmtory owel disese. Gstroenterology 126: , Rutter M, Sunders BP, Wilkinson KH, et l. Thirty-yer nlysis of olonosopi surveillne progrm for neoplsi of olonosopi surveillne progrm for neoplsi in ulertive olitis. Gstroenterology 130: , Velyos FS, Loftus EV Jr, Jess T, et l. Preditive nd protetive ftors ssoited with oloretl ner in ulertive olitis: se-ontrol study. Gstroenterology 130: , Askling J, Dikmn PW, Krlén P, et l. Coloretl ner rtes mong first-degree reltives of ptients with inflmmtory owel disese: popultion-sed ohort study. Lnet 357: , Nowki TM, Brükner M, Eveslge M, et l. The risk of oloretl ner in ptients with ulertive olitis. Dig Dis Si 60: , Rutter M, Sunders B, Wilkinson K, et l. Severity of inflmmtion is risk ftor for oloretl neoplsi in ulertive olitis. Gstroenterology 126: , Neurth MF, Trvis SP. Muosl heling in inflmmtory owel diseses: systemti review. Gut 61: , Vn Asshe G, Dignss A, Bokemeyer B, et l. Seond Europen evidene-sed onsensus on the dignosis nd mngement of ulertive olitis Prt 3: Speil situtions. J Crohns Colitis 7: 1-33, Rhmilewitz D. Coted meslzine (5-minosliyli id) versus sulphslzine in the tretment of tive ulertive olitis: rndomised tril. BMJ 298: 82-86, Fujii S, Fujimori T, Chi T. Usefulness of nlysis of ltertion nd oservtion of surfe mirostruture for dignosis of ulertive olitis-ssoited oloretl neoplsi. J Exp Clin Cner Res 22: , Chuert P, Benhttr J, Srg E, et l. K-rs muttions nd ltertions in neoplsti nd nonneoplsti lesions ssoited with longstnding ulertive olitis. Am J Pthol 144: , Eden JA, Arms KR, Myerry JF. The risk of oloretl ner in ulertive olitis: met-nlysis. Gut 48: , Rutter MD, Sunders BP, Wilkinson KH, et l. Severity of inflmmtion is risk ftor oloretl neoplsi in ulertive olitis. Gstroenterology 126: , Rutter MD, Sunders BP, Wilkinson KH, et l. Cner surveillne in longstnding ulertive olitis: endosopi ppernes help predit ner risk. Gut 53: , Rosenerg L, Lwlor GO, Zenle T, et l. Preditors of endosopi inflmmtion in ptients with ulertive olitis in linil remission. Inflmm Bowel Dis 19: , Velyos FS, Terdimn JP, Wlsh JM. Effet of 5-minosliylte use on oloretl ner nd dysplsi risk: systemti review nd metnlysis of oservtionl studies. Am J Gstroenterol 100: , Peyrin-Biroulet L, Ferrnte M, Mgro F, et l. Results from the 916
7 2nd Sientifi Workshop of the ECCO (I): Impt of muosl heling on the ourse of inflmmtory owel disese. J Crohns Colitis 5: , Cirns SR, Sholefield JH, Steele RJ, et l. Guidelines for oloretl ner sreening nd surveillne in moderte nd high risk groups (updte from 2002). Gut 59: , Mowt C, Cole A, Windsor A, et l. Guidelines for the mngement of inflmmtory owel disese in dults. Gut 60: , Kornluth A, Shr DB; Prtie Prmeters Committee of the Amerin College of Gstroenterology. Ulertive olitis prtie guidelines in dults: Amerin College of Gstroenterology, Prtie Prmeters Committee. Am J Gstroenterol 105: , quiz 524, Lutgens MW, Vleggr FP, Shipper ME, et l. High frequeny of erly oloretl ner in inflmmtory owel disese. Gut 57: , Bione L, Mihetti P, Trvis S, et l. Europen evidene-sed Consensus on the mngement of ulertive olitis: Speil situtions. J Crohns Colitis 2: 63-92, The Jpnese Soiety of Internl Mediine 917
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