Pathological Evidence of the Cause of Spontaneous Regression in a Case of Resected Hepatocellular Carcinoma

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1 CSE REPORT Pthologicl Evidence of the Cuse of Spontneous Regression in Cse of Resected Heptocellulr Crcinom Shunichi Mtsuok 1, kinori Tmur 1, Mitsuhiko Moriym 1, Hirotoshi Fujikw 2, Kenji Mimtsu 3, Tktsugu Oid 3 nd Mshiko Sugitni 4 bstrct 67-yer-old mn presented for n evlution fter experiencing right hypochondril pin lsting for two months. bdominl ultrsonogrphy showed heptic tumor in the right liver nd extremely mild heptic stetosis. The imging findings indicted tht the tumor (43 mm in size) ws ischemic, nd the lesion ws surgiclly resected nd exmined. The histopthologicl findings demonstrted 95% necrosis with modertely differentited heptocellulr crcinom (HCC). The dignosis ws HCC with spontneous regression. There ws lso pthologicl evidence of thrombus formtion in the peripherl rteries nd portl veins. In ddition, the non-cncerous regions of the liver were dignosed s exhibiting non-lcoholic stetoheptitis. The pthologicl findings obtined fter resection of the HCC lesion showed spontneous regression. Key words: heptocellulr crcinom (HCC), spontneous regression, rterio-portl thrombi, non-lcoholic stetoheptitis (NSH) () () Introduction pproximtely 85% of cses of heptocellulr crcinom (HCC) re thought to be cused by virus-induced chronic liver diseses. In recent yers, however, the number of nonheptic virus (HV)- nd non-heptic C virus (HCV)- relted cses hs been incresing. Reports of HCC resulting from non-lcoholic stetoheptitis (NSH) re prticulrly noticeble. In ddition, lthough rre, there re reports ech yer of cses of HCC with spontneous regression. In lmost ll of these cses, the HCC lesions re the result of virus-induced heptic disese. Concerning HCC with spontneous regression involving the peripherl blood vessels, mny reports hve provided evidence of rteril thrombosis, with few noting evidence of portl vein thrombosis. However, there re no reports of cses in which both types of thrombi hve been observed. In this report, we describe cse of HCC resulting from NSH in which the pthologicl evidence indicted spontneous regression cused by the presence of both rteril nd portl vein thrombi. Cse Report 67-yer-old mn complined chiefly of right hypochondril pin. He hd been receiving orl tretment with mlodipine in ddition to colestimide nd Glufst in the hospitl for hypertension nd dibetes mellitus, respectively. Due to his obese sttus, the ptient hd begun diet three yers erlier nd hd succeeded in reducing his weight by pproximtely 5 kg. The mild hypochondril pin ws not relted to dietry intke, nd he presented to our hospitl for his first exmintion fter his symptoms hd persisted for two months. On the first exmintion, only mild heptic dysfunction nd hypercholesterolemi were observed. However, since bdominl ultrsonogrphy showed n pproximtely 42-mm neoplstic lesion in segment S6 of the right lobe of the liver, the ptient ws hospitlized for further exmintions nd tretment. He hd pst medicl history of hypertension t 48 yers of ge nd dibetes mellitus nd Division of Gstroenterology nd Heptology, Deprtment of Medicine, Nihon University School of Medicine, Jpn, Deprtment of Gstroenterology nd Heptology, Socil Insurnce Yokohm Centrl Hospitl, Jpn, Deprtment of Surgery, Socil Insurnce Yokohm Centrl Hospitl, Jpn nd Deprtment of Pthology, Nihon University School of Medicine, Jpn Received for publiction pril 2, 2014; ccepted for publiction My 2, 2014 Correspondence to Dr. Shunichi Mtsuok, mtsuok.shunichi@nihon-u.c.jp 25

2 Tble. Lbortory Dt on dmission Peripherl blood WC RC Hb Plt Cogultion PT HPT 7,100 L 508 g/dl g/dl g/dl % % -15 M 9.1 % iochemistry ST LT LDH LP T-il T-cho T UN Cre P- Hb1c IgM Ig N M Fe ferrtin 35 IU/L 43 IU/L 180 IU/L 235 IU/L 52 IU/L 0.8 mg/dl 231 mg/dl 138 mg/dl 18.7 mg/dl 0.86 g/dl 119 mg/dl 5.4 % 1, < mg/dl mg/dl mg/dl g/dl ng/ml Heptitis virus mrker Hs g Hc b HV - DN HCV b( 3rd ) HCV - RN HIV b Tumor mrker FP 11 ng/ml (L3 25.7%) PIVK II 6 CE 1.5 ng/ml C U/mL Figure 1. bdominl ultrsonogrphy ( mode) showing mm solid tumor protruding down from the right posterior inferior segment of the liver, with n echo-poor mosic pttern. heptic dysfunction due to heptic stetosis t 55 yers of ge, with no history of trnsfusion. He hd no history of lcohol consumption or smoking nd no fmily history of note. t the time of hospitliztion, his height ws 152 cm, his body weight ws 59 kg nd his body mss index (MI) ws In ddition, his body temperture ws 36.7, his blood pressure ws 152/94 mmhg nd his pulse rte ws regulr t 76 bets/min. The plpebrl conjunctiv showed no signs of nemi, nd there were no plpble superficil lymph nodes or yellowing of the bulbr conjunctiv. No rles or murmurs were detected. The ptient s bdomen ws flt nd soft, without plpble liver, spleen or msses, nd no signs of scitic fluid were noted. Mild tenderness ws confined to the right hypochondrium. There ws no pretibil edem. The ptient s lbortory findings on dmission were s follows (Tble): totl bilirubin (T-il) =0.8 mg/dl, sprtte minotrnsferse (ST) =35 IU/L, lnine minotrnsferse (LT) =43 IU/L, lkline phosphtse (LP) =185 IU/L, lctse dehydrogense (LDH) =236, γ-glutmyl trnspeptidse (γ-gtp) =52 IU/L. In ddition, mild heptic dysfunction ws observed, with totl cholesterol (TCHO) level of 231 mg/dl. Known heptitis virl mrkers, including those for heptic virus (HV) nd heptic C virus (HCV), were negtive. The concentrtions of ntinucler ntibodies nd ntimitochondril ntibodies were elevted t 40x nd less thn 5, respectively. The hemoglobin 1c (Hb1c) vlue ws 5.1%, thus indicting fvorble glycemic control, nd other fibrosis mrkers nd ferritin prmeters were within the norml rnges. Tests of tumor mrkers showed n lph fetoprotein (FP) level of 11 ng/ml (norml: 20 or less) nd mildly elevted FP-Lectin 3 frction of 25%, while other test results were norml. The bdominl ultrsonogrphy ( mode) findings re shown in Fig. 1. The size of the liver ws norml, lthough the slightly irregulr surfce nd blunt borders indicted pttern of chronic liver dysfunction. 42-mm 45-mm solid tumor ws observed protruding down from the right posterior inferior segment of the liver, with n echo-poor mild mosic pttern. There were no hlos, nd no spleen enlrgement, scites fluid or collterl circultion were noted. There were lso no biliry, pncretic or renl bnormlities, nd no lymphdenopthy ws observed in bdominl res. The ptient s clinicl course fter dmission ws evluted using contrst-enhnced ultrsonogrphy of the heptic mss, in which erly vsculr phse imges showed no contrst enhncement, wheres post-vsculr phse imges showed deficiency (Fig. 2). s on contrst-enhnced ultrsonogrphy, contrst-enhnced bdominl computed tomogrphy (CT) showed no dense stining on rteril phse imges (Fig. 3). In ddition, the bdominl ngiogrphy findings showed no dense stining in the cncerous portions of the liver on erly vsculr phse imges (Fig. 4). sed on these imging nd hemtologicl findings, the possibility of typicl HCC, intrheptic bile duct crcinom or Hodgkin s disese ws considered. However, no definitive digno- 26

3 Figure 2. Contrst-enhnced ultrsonogrphy of the heptic mss: Erly vsculr phse imges showed no contrst enhncement (), while post-vsculr phse imges showed deficiency (). Figure 3. Contrst-enhnced bdominl CT showed no dense stining on rteril phse imges (), while dense ringshped stining ws observed t the periphery of the mss on portl imges (). tl vein thrombi hd formed, s shown in the schemtic figure (Fig. 5C). Liver injury in the non-cncerous portion ws cused by chronic heptitis. The pthologicl findings showed cpsulr invsion with trbeculr pttern of structurl typi in the vible tumor, with poorly differentited HCC nd pseudotubules in some prts (Fig. 6). Necrosis ws detected in most of the regions thought to be cncerous, nd ghost cells suggesting heptocytes were observed, s well s grnultion tissue formtion due to the prolifertion of fibroblsts, collgen fibers nd mcrophges (Fig. 6). In the non-cncerous portions, ft deposition in heptocytes ws observed in less thn 30% of the whole specimen, nd there ws very mild inflmmtory cell infiltrtion in the portl vein nd heptic mesenchyme. The lobulr rchitecture showed deformtion due to the effects of fibrosis between the centrl veins nd the centrl nd portl veins (Fig. 6C). The pthologicl dignosis ws modertely differentited HCC type eg, fc (+), fc-inf (+), sf (+), s1, vp1, vv0, v0, b0, im0, sm, ch.pericellulr nd perivenulr fibrosis ws lso observed, in ddition to slight bllooning degenertion. Fibrosis, bllooning nd other fctors, such s NSH ctivity score (NS) of 4 points, Mtteoni clssifiction of type 4 nd runt clssifiction of grde 1, led to dignosis of stge 3 NSH (Fig. 6D). The intrtumorl vessels contined fresh blood ( ) nd orgnizing thrombi ( ) Figure 4. bdominl ngiogrphy findings showing no dense stining in the cncerous portion of the liver on erly vsculr phse imge. sis ws mde, nd segment 6 subsegmentl resection ws subsequently performed on dy 18 of hospitliztion. The mcroscopic findings of the resected specimen re shown in Fig. 5. The tumor mesured 42 mm 43 mm in size, ws brown-green in color nd exhibited cpsule formtion. Most of the tumor ppered to be necrotic. On mgnified imge (Fig. 5), the tumor ws observed to be touching the cpsule. Subsequent findings indicted tht most of the lesion ws necrotic due to cogultive necrosis, nd por27

4 HCC grnultion tissue necrosis p p p C : Smll rteril thrombus p : Portl thrombus Figure 5. Mcroscopic ppernce of the resected right liver tumor. : The uneven irregulr surfce of the non-neoplstic portion of the liver showing chronic heptitis nd cpsule formtion with lrge 42mm 43mm green-brown tumor contining blood vessels. : Mgnified imge showing the tumor touching the cpsule, with findings of cogultion necrosis in most of the tumor. lood vessels corresponding to thrombi formtion in the portl vein. C: Schemtic figure of. CV C CV D E F G H Figure 6. Histopthologicl findings. : Modertely differentited HCC with vible tumor exhibiting cpsulr invsion, trbeculr pttern of structurl typi nd pseudotubules in vrious loctions. : Necrosis in most of the re thought to be the tumor, with ghost cells suggesting HCC. Fibroblsts, collgen fibers nd grnultion tissue resulting from n incresed number of mcrophges were observed. C: Distortion of the lobulr rchitecture due to the presence of fibrosis between the centrl veins (CV nd between the centrl nd portl veins). D: Very mild inflmmtory cell infiltrtion in the portl re nd prenchym of the liver, with slight bllooning degenertion ( ). E: Fresh thrombi ( ) nd orgnized thrombi ( ) in the portl vein in the tumor. F: Elstic vn Gieson (EV) stining in the sme in loction. G: Nrrowing of the peritumorl rterioles ( ). H: Nrrowing of the peritumorl portl vein brnches ( ). 28

5 (Fig. 6E). In ddition, Elstic vn Gieson stining (EV stin) of the sme site demonstrted nrrowing of peritumorl rterioles ( ) (Fig. 6F, G), nd pre-cirrhotic chnges were observed in peritumorl cells (Fig. 6H). Consequently, the dignosis ws confirmed to be HCC due to chronic liver disese ginst bckground of NSH with necrosis in most of the tumor (95%) s result of thrombosis in the surrounding heptic rteries nd intrheptic portl veins, leving just 5% of the tumor vible. The ptient s postopertive course ws fvorble, nd he ws dischrged from the hospitl 11 dys fter undergoing surgery. He hs since visited the hospitl regulrly for over three yers, with no signs of recurrence. Discussion In mjority of cses of HCC, there is bckground of chronic liver disese cused by HV or HCV. Recently, however, there hve been mny reports of cses resulting from NSH. The present cse involved non- nd non-c HCC with presumed coexisting NSH bsed on the ptient s clinicl course nd medicl history tht included bnorml glucose tolernce, hyperlipidemi, hypertension nd obesity. The ptient s NS ws 4 points, his Mtteoni clssifiction ws type 4 nd his runt clssifiction ws grde 1, stge 3 (1-3). Fibrosis ws more conspicuous thn ft deposition. ccording to the preopertive blood pltelet nd indocynine green (ICG) vlues, he ws thought to hve non-cirrhotic liver; however, cirrhosis ws verified pthologiclly. There re severl previous reports of coexisting HCC in cses of non-cirrhotic NSH (4). In the present cse, the findings showed necrosis in most of the tumor, with just smll portion remining in the cpsule, indicting prtil spontneous regression of the HCC. In ddition, the histologicl findings showed the presence of fibroblsts, histiocytes nd other grnultion tissue surrounding n extensive nd orgnized necrotic focus. We therefore conjectured tht this observtion ws reflective of response to the progression of necrosis over time by biologicl processes recting to the development of cogultion necrosis. Theories hve been put forwrd concerning the role plyed by embolism nd fctors of infection, immunology nd the spontneous regression of HCC. For exmple, Imok et l. expressed the pthologicl opinion tht spontneous regression in resected HCC is due to nutrient vessel embolism cused by the ccumultion of cogultion necrosis debris (5). In ddition, Yno et l. reported totl of 28 cses of spontneous regression of HCC, including one treted by their group. The cuse of regression ws unknown in 16 of the cses, wheres, in four cses, the cuse ws identified to be blood flow disorder, with pthologicl proof of rteril embolism only in the study by Imok et l. (6). In the present cse, lthough the mcroscopic findings did not show fresh nd orgnized thrombi in the thick portl vein penetrting the tumor, such lesions were observed in the pthologicl findings. Orgnized thrombi nd recnliztion were lso observed in the peritumorl rterioles nd portl vein. Furthermore, the histopthologicl findings showed no necrosis of norml heptocytes in the necrotic portions, lthough heptocyte ghost cells nd findings suggestive of postopertive heptic rtery embolism were noted. However, no ngiogrphic techniques were performed in this cse; therefore, such procedures could not possibly hve cused the ptient s symptoms. We speculte tht the necrosis in most of the HCC mss ws the result of the formtion of thrombi in nutrient vessels for n unknown reson. In other words, it ws strongly presumed tht, rther thn being spontneous clinicl condition cused by the mixture of old thrombi with tissue, the necrosis ws the product of grdul thrombi formtion in the peritumorl rteriolr wlls, cusing luminl nrrowing tht led to ischemic chnges. In this cse, thrombus formtion ws observed in brnch of the portl vein, nd the peritumorl hemodynmics were estimted to be extremely complex. The schemtic drwing presented in Fig. 5C shows the res of necrosis, grnultion tissue nd vible tumor tissue, with conspicuous grnultion tissue in the region with numerous thrombi. In ddition, irregulr regenertion ws observed in heptocytes in the noncncerous res. The genertion of morphologiclly different cell popultions due to chronic liver injury resulting from HCV hs been hypothesized. In other words, tht process of repeted necrosis nd regenertion lies t the hert of crcinogenesis (7, 8). However, there hve been no reports of this issue concerning NSH ptients. The reltionship between irregulr regenertion nd NSH should therefore be exmined in the future. The cuse of grdul thrombus formtion over time is unknown; however, the possible influence of orl medictions nd cytokines secreted by the tumor itself hs not been determined. In generl, terms such s spontneous recovery nd spontneous remission re used to describe the spontneous regression of tumor, lthough it hs been reported tht spontneous recovery occurs in only pproximtely one in 10,000 cses. Renl cell crcinom, neuroblstom, choriocrcinom, mlignnt melnom, bldder crcinom, leukemi nd some forms of Hodgkin s disese, s well s brest nd other cncers, ccount for 70% of these cses. lthough theories of immune ctivtion, hormonl effects, poptosis, differentition nd other fctors hve been proposed, no definitive nswers hve been found; opinions concerning HCC re prticulrly scrce. This report describes cse of resected HCC with bckground of NSH involving 95% tumor necrosis. The coexistence of old nd new rterio-portl thrombi hs been pthologiclly verified, nd this phenomenon is thought to be potentil cuse of the spontneous regression of HCC. The etiology of thrombi formtion is unknown. However, if it cn be proven tht these lesions re the result of the ctions of orl medictions nd/or cytokines, such findings would suggest the need to switch to moleculr-trgeted therpeutic gents s tretment method. In this report, we described cse of HCC tht resulted 29

6 from non-lcoholic stetoheptitis in which pthologicl evidence indicted spontneous regression due to the presence of both rteril nd portl vein thrombi. The uthors stte tht they hve no Conflict of Interest (COI). References 1. Mtteoni C, Younossi ZM, Grmlich T, et l. Nonlcoholic ftty liver disese: spectrum of clinicl nd pthologicl severity. Gstroenterology 116: , runt EM, Jnney CG, Di isceglie M, et l. Nonlcoholic stetoheptitis: proposl for grding nd stging the histologicl lesions. m J Gstroenterol 94: , Kleiner DE, runt EM, Vn Ntt M. Design nd vlidtion of histologicl scoring system for nonlcoholic ftty liver disese. Nonlcoholic Stetoheptitis. Clinicl Reserch Network. Heptology 41: , Ytsuji S, Hshimoto E, Kbutke, et l. Heptocellulr crcinom rising in non-lcohoic stetoheptitis (NSH) without dvnced fibrosis. Hep Intl 1: 22, Imok S, Sski Y, Msutni S, et l. Necrosis of heptocellulr crcinom cused by spontneously rising rteril thrombus. Heptogstroenterology 41: , Yno Y, Ymshit F, Kuwki K, et l. Prtil spontneous regression of heptocellulr crcinom: cse with high concentrtions of serum lens culinris gglutinin lph Fetoprotein. Kurume Med J 52: , Shibt M, Morizne T, Uchid T, et l. Irregulr regenertion of heptocytes nd risk of heptocellulr crcinom in chronic heptitis nd cirrhosis with heptitis-c-virus infection. Lncet 351: , Ueno Y, Moriym M, Uchid T, rkw Y. Irregulr regenertion of heptocytes is n importnt fctor in the heptocrcinogenesis of liver disese. Heptology 33: , Morimoto Y, Tnk Y, Itoh T, Ymmoto S, Mizuno H, Fushimi H. Spontneous necrosis of heptocellulr crcinom: cse report. Dig Surg 19: , Heinn J, Miyuchi T, Suzuki T, Ishid H, Hshimoto M, Wtri J. Spontneus regression of multiple lung metstsis following regression of heptocellulr crcinom fter trnsctheter rteril emboliztion. cse report. Heptogstroenterology 54: , The Jpnese Society of Internl Medicine 30