Document 1Q2174Z0wDbGEyMgq3amD9gE

.V 1 APOOO14636 Voi. sya So. i VINYt.-Cl Vc- -C&fttS X/ ( -yy <'HIDE-INDUCED LIVER DISEASE -- TIIOMA T AL VINYL-CHLORIDE-INDUCED LIVER DISEASE j 17 / , From Idiopathic Portal Hypertension (Banti's Syndrome) to Angiosarcomas ^ I .oils !'>. Thom w M.D.. FI \\s Poim'J.k. M.D.. Pii.D.. I'.u i. D. Berk. M.D.. Ikvim; Si i.iurnr. M.D.. as:. Hew r v! x. M.D. Abstract H stoiogic exa.Tination ol liver tissue (eight autopsy and 18 biopsy specimens) and five spleens from 20 workers wart v.ny! ehlories oolymerizatton st.%s3 hepatic angiosarcomas <n to. In addition, a peculiar pattern of progressive portal-tract, mconspicuous intralobular and conspicuous capsular fibrosis was observed in the five workers without angiosarcoma, in all the seven patients with angiosarcoma from whom tumor-fres portions of the liver were available, and in two tumor-free biopsies from patients subsa- quentiy found lo havs angiosarcoma. Th? fibrosis was accompanied by splenomegaly. Hypertrophy and hy perplasia of both neoatocytes and hepatic and splenic mesenchymal ceas were also seen. The histologic Simi larity to chronic inorganic arsenical poisoning, in which angiosarcomas also occur, and to idiopathic portal hypertension (Band's syndrome) suggests that the latter syndro'me at times results from unknown tox ic. possibly environmental, chemicals. (N Engl J Med 292:17-22.1975) .t h' THF. development of Itopitic angiosarcomas in work ers expos'd lu vinyl chloride gas in the manufacture Maltoni*0 subsequently described angiosarcomas of the liver and other organs as well as nephroblastomas in ruts of polyvinyl chloride Jus been well documented.'* Hisio-exposed to vinyl chloride gas. Recently, angiosarcomas of logic study of Ivtutic and splenic specimens taken*!rom suchuorkeri stK^cstsui us. moreover, th:u other diseases the liver have been seen in mice alter exposure to as little as 50 ppm of vinyl chloride.11 that have not in the past been related to industri.il ex When specimens of human angiosarcoma from vinyl posure muvjjgjiiyofyed. Specifically. n case will be made chloride polymerization workers were reviewed in the for the concept that splenomegaly with portal hyperten Laboratory of Pathology of the National Cancer Institute, sion associated with slight hepatic fibrosis. previously des the lesions in areas uf the liver not involved by an ignated as Banti's syndrome,4 may be the result of ex giosarcoma appeared similar to alterations recently re posure to known or unknown chemical agents. ported in vinyl chloride workers in Germany.** in these History or Tr Vinyl Chloride Liver Injury patients inconspicuous portal and perisinusoidal fibrosis was associated with impressive hepatic capsular fibrosis as Polyvinyl chloride, one of the must widely used syn seen by perit^"`*icoj>y. Hepatic-function te* wealed thetic plastics, has been manufactured for more than 40 vears by polvmerization of gaseous vinyl chloride in dte United Staie* and in many other countries. Concern about untoward side effects in workers had centered variable abnormalities. Clinical manifestations included portal hypertension with splenomegaly, thrombocyto penia and bleeding esoplugeul varices. This German re port focused our interest on the appearance of the liver primarily on a disease, ncro-osteolysis,1 which is charac not only in patients with hepatic angiosarcomas but also in terized by Raynaud's syndrome, dermal induration and other workers with ftepatic fibrosis exposed to vinyl chlo bone lesions. Two reports^ also dealt wills nonspecific alterations of hepatic structure and function, and a lesion designated "chronic epithelial hepatitis" was found in ride who had been diagnosed as having cirrhosis because of portal hypertension, vnriceal hemorrhage and spleno megaly.' about 25 per cent of die examined workers in Russia.* Hepatic abnormalities, which did not attract major atten By coincidence, tliere have been several recent reports of portal hypertension without obvious cause in patients tion. Ijccume far more important because of the discovery with psoriasis who had i eceived an inorganic arsenic of three can's of angiosarcomas of the liver, an mliei wise preparation. Fowler's solution, for prolonged peri- very rare minor, in workers in a polyvinyl chloride pro otk,3 s These observations were interesting in view of duction pl.uit in this l ouinrv.1 The imriKlm iion of a sur earlier reports from Germany ami France of hepatic an veillance system in iliis plant dciettcd a total of sevencases of hepatic angiosarcoma.'* Animal experiments confirm giosarcomas developing in vintners exjvoscd to insecti cides containing inorganic arstiic.u Roth's report in die relation between hojxuic angiosarcoma anil exposure cluded -17 workers with chronic arsenic intoxication, Of lugaseous iim/chloride. In 1P7I. Italian mu*.vtig;iior>re ihfcc, foul li.ul hepilic carcinomas, five had sarcomas fan ported that pi o longed inhalation nl vinyl chloride pro- giosarcomas). ami l;l of 27 atUopsied by him had unusual rimed carcinomas of the /ymli.il gland in r.us.1* ami ty peso) cirrhosis.'* Fram ihc t_K>r.i.irt .! t*.etjali'?. N.iiion.it Cancer Instuutc. N.norul ln-iiru*<->[ Mv.a.h, H.-iIic-C.., VIP. thr Mount .`-in 11 ScNviliif M cilicinc-if the t il. rmtcj-in nr Nc* 'tuck.NV. the S.*,:i.ii ..ji l>ic.ise>of thi.-Li-i.-i. 'siw..i Jn-I..';! ol' .Vst-::i-. Ms'i.<K>lisin ..nJ [>:-.-*siivir ihst-.t-tfs. S.i- li.in..' In-;.1 HU'-.<11i.'.il:h. h.'ifM-.u, MII. .ii'.l ih.1t -.ii.ir.uiJ liirlfi IH-Iitt. j; I -.J.o-Ui.ii'v't. t V:u .. !.-r Pl.lMSf tortllol. .VI.lGt.l. li V bill's- iv'poni :> 11, lli.nv.-- >! S.Oiiin.ii C'jn-cr lua^ 11-.. ...It: v: i. u.-aw.-... mp:-hui Pi IMnwi l .`.Mr:*. >.!'! if in Ki-ni.L'm.i.-, I'wO-irv. lmcrn.tlion.tl Ccn- l.-i, S I'.mii.it IU.m'.I- Material Studied Tin* ohM'rt.ttmm ivomicil litre .tie luted mi the study of lie- pitii li-uio obtained [mm 20 vioikcrs wlu h;ul imUi-.ui.il e,s- vim 11 Uloi jilt It ii' potli.ii^tii jivi iixK. iiMiatlv tutnlitii' inn vr.u - .inti i virmlinu >i|> to l-S m*;ii -, Tlu* tl-Miv- weie l*i itrcl Ikhii I "> |i.iiii'niN v.ii Ii ivniii .uni live with lit pit i< liln in. Iiui i./ili.iui .m.i, Tlic iii.iftn in ol lln -c -|K-< ni.rvi- i>i imli.illi tilii.inutl. -rutlii-il. .mil in mint i.i--'% u'jhhu-i! It. tilli n'.1 J Inn .ill i>fit Milumitvil i`*(lit 1.,iLmiiatoiy il 1'.ulioS><gv, N.i- APObOf4637 -HK NFAV F.NCl.ANb JOURNAL OF MKIJ1CINF Jan. 2, 107.3 '. s. Si , -.7 ix*. Figure i. Hepatic Artg iosarcoma in a Worker Engaged in Polymerization of Vinyl Chloride. A shows sinusoidal pattern progressing lo a papillary pattern (straight arrow) (hematoxylin and eosin stain x 100). Note envel oping tumor cells separated by widened tissue space ol Disse (curved arrow). B shows small cavernous spaces with transition to anaplastic growth in angiosarooma in the upper part of the photomicro graph and liver-cell pistes enveloped by sarcoma cells in the right lower corner (hematoxylin and eosln stain x 100). tioiul Cancer Institute, for review. Recalle of the nature of our access to ilte material, ilicsespeciuiensdonoi represent a consec utive series and cannot l>cconsidered to indicate!he reUthe fre quency of these vinyl-chlorkle-associ.itcct lii-pa tic lostons. Twenty specimens from the IS jutiems with angiosarcoma were reviewed, and IK rtf these (right autopn and 10 biopsi). showed ansriosurcuma. In addition, two of these patients hud pre vious livvr biopsies tli.n (tad been obtained six and three months before dor diagnmiiol Iwjntk angiosarcoma was made. In sewn of the patients (four uuto])-) and five biopsy specimens) sufficient liter tissue w;is |>re*vni outside die angiosarcoma and free r*f pressure effects inpt-itnii ;ui oval nation of die mnrpliolug) of the tuinor-fice portionsitfiiteliver. laser iismu* was obtained In biopsy I fit e stirgicul und one ncedk-b'ops-v it|Kxiim-U'.) in the fixe patients with hepuk. iibriiMS whlmm known utiginsamima. In one patient in wlnnu lirp.ua fibnras h.itl lceiH>l>HTved in an iititi.il mu gkal itiopsy specimen, a fo!li>w-u]> iiiviUe l>inp%\ was obtained dm ing jm.-i itoiteosiopv aficr an intenal >>l iw.i sears, itie |>atiem lias ing had no lurtliei expoMiu" n vim ft itior idc Ohscis.iiimis nf die splenic changes wt-te made on thtce surgh al and i wo auiop^s spe imens. All spitmicns wete fixed m (twm.ihn .mtl sindiixl bs t unsvuiioii.d mkinso>|maI Us lHits. Observations Angiosarcoma Although the jiie'cmi' ol anu.ins.tt minus in \iti\l 11!>- tide wen ket s lias piet imtsk been topni ted. the hislolngu hai a< H i i't ii % id the i mix m s .ne brie!I\ < ! -- ihed in ,ui .\t- tcm;>t ;> distinguish litem In.in hejMik .uigiosaimm.t- apparently not induced by chemicals and to trace their possible relation to iIk fibrottc lesions. Three basic pat terns, listed here in order of frequency, were seen in dif ferent parts of the angiosarcomas. Tiie first, the sinmahlnl pattern, was characterized by focal, often nmhicentric. dilatation of sinusoid*, with hy pertrophic and hyperplastic sarcoma cells forming a lin ing for the dilated sinusoids. The sarcoma cells enveloped liver-cell plates and bile ductules and infiltrated fihrmic portal tracts (Fig. l.i). The enveloped hopatocytes were usually hypertrophic and hyperplastic anti ihuapjK*ared its cords around dilated bile cuivalicnli. which often contailietl hiie plugs. IzHisciy arranged ivticulm and collagen filn-rs were present in the widened tissue sjwc of lh*se to gether with increased numbers of Jxon-nenplastic-apjK'aring Fibrnhiasts.md macrophages. Tiie second, the pattern. liad larger and move irregular vascular spues. Loose strands of hepi lie eon Is enveloped hv sarcomatous cells projected into these spaces. Antipin- and disappearance ol hepaiii cord cells developed, with inci cased fihiosisol tiie widened spue ol Disse. The third, the (muimin pattern. was rltaracteri/eil In even l.itger. hluod-lilied |i;is stinmindvd In iliiik, ii- htnlit Hallsluicdln vtitoinaioiiscellsfFit;. Hi). 1 ti .uii It ii- hi. one loin i h til i he <ingios.it com.is h.itl nun e solid nodules of anaplastic sanoniu. I liese nodules out- t AP00014638 Vol. 292 No. 1 V1NYI.-CP UDt ISDUCtO UVKK DISEASE -THOMA* "T AL. 19 proved lit? surrounding pnremhvmj, arid in one tumor, uiiapiasiic sarvonnt cell* invaded |*>ri,il-vein brunt lies, 1-^.u dilatation of sinusoid* with pmlilcTatinii arid ciii.;: icvtit mJ the sinusoidal tells associated with pt*ri^i- ->i.!u,u mm-M-ni .tnc.trK M-i-^r hi the cvolte i-i'll.i 1 his I> sj.<n v%,i noirti m of the tumor-lice loci [jcliihciis from patients with ;^i' ii.i! miiu. .liul in t Ik- two biopsies taken before aiv^nI'.iKtinsa w.isdeteited. li was jlsoohservrdin twopa tient- mi whom .m^iMs.irumni has not developed. and in whom, accordingly, careful follow -up observation is indi cated. In the patient* with angii>sam>m;i. some o( the si* mitoidul lining cell* hud enlarged, atvpical nuclei and bul ky cMopluxn that was PAS negative in contrast to many of the lining cells in the uninvolved parenchyma (Fig. 2). There were gradual mmsittom Iwtwcen the areas of focal dilatation of miuisomU to multiple, microscopic-sized an giosarcomas with a sinusoidal pattern. In three patients other organs besides the liver were in volved by angiosarcoma: the duodenum in one, the lung in a second, and Use lung, heart, kidney and lymph nodes in a third patient. Hepatic fibrosis1 All the livers without angiosarcomas and the unin volved portions of die livers with angiosarcomas showed Fipur* 2 Focal Dilatation oi Sinusoids, wun Hyoerpiastic Hroatocytes (Arrow) and Excess Sinusoidal Unmet Calls. So'".? .vi;n Hvpefchromntic Nuclei (This Acceptance Con trast* with That oi Normal Sinusoids in tne Ri^nt Lower CornBr)(Hematoxylin and osm Stam * i60j the same basic changes, the extent of which varied widely within each specimen. Kxcess fibrous connective tissue caused variable enlargement of most portal tracts (Fig. J.-f). A rii.MiiH.tive feature wax the tendency for single liop.no> i n - .uid groups of hopatoev cos ,n ihe mar .jins of tlie : a:.i! i:.ii!> |o In' sep.iv.ned Imm adtutcut hepatic coni ieli> and surrounded by tills projji cssise hliiosis. IViiltivKiiiiuiol bile ducts was noted in these fibroiit portal tracts togedier with a variable in filtration of hinplimviis, Occusiniulh. the walls oi porial-vein brunches showed futul fibrosis. Adjacent portal tracts were often connected by connective-tissue septa in the sense of a perilobular fibrosis and some thin septa traversed the parenchyma and extended irregularly toward central veins. In two cases, both with angiosarcomas elsewhere in the liver, these septa separated pansof the parenchyma to produce nodules. The hepatic capsule showed focal thickening and nodular Hbrotic areas that often extended into subcapsular hepatic tissue to connect with adjacent portal tracts. The sinusoidal lining cells were focaily increased in number, especially in areas where sinusoids were dilated. Intralobular, perisinusoidal fibrosis, though inconspicu ous in heinaioxylin-eosin-stained sections, could be dem onstrated in these areas by special stains for reticulin and collagen fibers. In otherareas, groups of hepaiocytes, with no particular intralobular localization, varied conspicu ously in cellular and nuclear size, many of them being dis tinctly enlarged (Fig. Jfl). Binudear and multinudeate hepaiocytes. some with much cytoplasm, were intermixed with a few hepaiocytes that were smaller than normal. De generation and necrosis of hepaiocytes. although present, were not more conspicuous than in any routine surgical specimen, in the second biopsy specimen, obtained in one patient two years after cessation of exposure to vinyl chlo ride, these abnormal changes in both hepaiocytes and si nusoidal lining cells hid disappeared, but the capsular, portal-tract and intralooular fibrosis persisted. Splanic Changas The available spleens were large, weighing 560 to 1050 g, and showed on cutsection enlarged Malpighian follicles and a firm, beefy red pulp. Microscopically. the follicles were hyperplastic and had large germinal centers and wide perifollicular zones (Kig. 4). Occasionally, fresh hem orrhage teas found around penicillury arteries and folli cles. The red-pulp sinuses were witlened and often lined bya continuous layer ofcuboidal leticuloettdotltelciUells. The slightly thickened pulp cords contained mam lym phoid and histiocytic cell* us well ;u erythrocytes. Fibrosis of the red piilpwasabseni t>r inconspicuous, ami hemosiderinopltagcs wcreonlyttccasionaUyseen. Discussion The relatively frequent development of hepatic angio sarcomas iti workers engaged in tlie polymerization nl ti nt I chloride Has now lteen cMuhlislied. lit this rojmrt die emphasis is on a {H*euliar hepttu' fibrosis in cm It woi kers and its rein ion km lie angiosarcomas. This fibrnsis. whUh s to repu'seut a second hepitic lesion atn tin liable to vtwl chloride e\[v>nrc. was lomul in the iiiimn dne 20 THE NEW ENGLAND JOURNAL OF MF.DL Jan. 2. 1075 Figure 1 Subcapsular Portion of a Surgical Specimen of the Liver of a Worker with Portal Hypertension. Note A the focal fibrotie thickening of the capsule and variable fibrotic enlargement of the portal tracts with fibrous connec tive tissue extending between periportal liver-cell plates. The lobular architecture is intaet (heractoxylin and ecain stain x 25). G shows indistinct groups of hepatocytes with enlarged cytoplasm and nuclei, sometimes binucleate. particularly in the upper pert of the photomicrograph in eontrest to smell hepatocytes. In pieces the sinusoidal lining cells are somewhat enlarged (ar row) (hematoxylin and eosin stain x18Q). portions of the liver of patients who had or were subse quent])' shown tohave angiosarcomas, and atso in patients without angiosarcoma who came to attention because of splenomegaly and manifestations of portal hypertension. The fibrosis is characterized by a conspicuous, focal capsu lar fibrosis, which is most impressive on gross inspection and was demonstrated in German workers by peritoneos copy.11 by a variable and irregular fibrosis of portal tracts, and by inconspicuous areas of intralobular, perisinusoidal fibrosis, This fibrosis is topographically related to prolif eration and activation of sinusoidal fitting cells and cells in the {issue space of Disse. These changes are associated with focal hypertrophy and hy|x:rp].isin ut Iwpatocvtes. The hepatneues are not .severely injured, nor h reactive intralobular itilLun mation seen. The apparent imegritvof llte hep.mxvtes explains win hepatk' tests that indicjie lu'p.mx ell nlaralierat tons v ield erratic or even normal re sults bull is st.iie.r'l!'l'tiese tests, therifoi e. cannot he de pended tqx mi to deret I the hepatic fibrosis. In llte spleen pioltln.mnii ol Kinplioitl ami tem ulnemlmhclial cells is observed, hut libn wish uni seen. Although the 4 hat . ret isi < hepatic fihiosis w.is pres, eut in alU.tsc'oi .ingioviHoma in whit Iadequate hepnit lissin was available. ihere is no e\ idem i- I h.u all tases ni hepaiiv libroo pinned lo.mgios.iiiomas, In the wot kers engaged in the polvmerization of vinyl chloride who were studied by us. the combination of hepatic angiosarcomas and fibrosis was more common than the fibrotic lesions alone. In other studies of workers exposed to vinyl chlo ride in Germany.4* Romania,1 and Russia* the fibrotic le sions without angiosarcomas have been more frequent, and a survey in this country revealed an increased inci dence or splenomegaly in such workers, dependingon the duration of their exposure.17 The relation of the fibrotic lesions to the development of angiosarcomas rx|uireftirt)ier study. However, a tran sition from tin.* fibrotic stage to angiosarcoma is suggested by theJocal proliferation ixrihof the sinusoidal lining ceils and of the hr|iuincyie<ith:it is seen in i he fibrotic stage hut becomes even more pronounced in the initial stages of an giosarcoma development. Further progression is indi cated by proliferation and piling up of atypical, samimaimis-appearing sinusoidal and perisinus<tidal cells that envelop proliferated hrpauxyies in t he areas of sinusoidal dilatation. These features. which elta ratteri/e tin* tmilticentric angiosarcomas with a sinusoidal pattern, can lw traced ftntber to the angiosarcoma*, with pupillarv and cavernous giowth patients, in ouiv a few cases. omlttlcs comjHtsed of anaplastic sartonia cells are*lwerved. Thus, ihe evolution of tin* hejxuk lesions ;uul the enlargement i I AP00014640 I*?frlOOOdV Tiftl `t l-lMMl'l l*| |rihH/\ pr.viv Iip |> :<H<iuiao va :t|i*uiMqUi<' ii|.asij i.sp .nioi/tiiajJ { ItlHlkMlIljajN fitSns IAji 1')ipn/unl .V| :<J AUiW.'j.Vl lUs*;|l-J-y (,) Ufil "C>`U | j" | ojj j.vnJO 'pijo|t|.i |.uih ii nauisj pui' 5 -vSun; "ui'i*. irj jo Atuodxnj niuario.Mio :y y '-jj f, j Llll V|\Vf ' lUl'til U<!)IVlJAkU1tlld.'>plJ0m.1 IMIIA I' fSJ.VlJ^Vi I 3mouib 5*cjsip AfiniAH is \AO Mw*M -1f 'If H^U `H 1IM X 3 i%r!i,:*i9::KojoAinpw *i<u!ip 1 sjruopi?nt *rtp iwpc|tu up pnr| :w nn^et^A *1 uwafaJQ 'I n!jnS X . ' 96l . 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