Document RJDV18Mg7ozdwRk0BN3dvwM4z

ntao Coitman |at (in hi*, ' anen*c- ^^aganh c Angiosarcoma Associated with hort-Term Arsenic ingestion iency 13 a - ttwestxq^ resent j and I lationsnioB^ itaoiisheo (aj, he pica Ism s of clay, t. jmCS w. roat. mo. .. fffgxD WALD. MO. ' iggiveY NCNDS.OW, MO. amern I. PATAKt. MO. i%wyAenii ^ comMas* ncemed am t but wee rw raving mM tn a 45 year old man. hepatic angioaareoma developed 33 years attar medicinal arsenic ingestion of only six months' duration. In addition, the patiant had a history of basal cad carcinomas without having had excessive sunlight exposure. Factor VIII staining of the tumor sup ports an sndothsllal ceil origin of the tumor. The development of skin cancers and hepatic angiosarcoma In this patient suggests that there may be no safe threshold of arsenic exposure. A careful history concerning even short-term arsenic exposure in ail patients with hepatic angiosarcoma may uncover more examples of this asso ciation. `and die pip 9 to inqtarim isfy a< ometophegli iy. and starts > to iron-dafr supplying is vMA 1959: 20! dciayingmiw mm 1970:12t 1977: 29S: of MnSckw wvt PsXioiopr, University of PUMm^i PWiOwpV Fonmylvonio. > tar reprints shoMd be addrousd to Or. Wold. MonMflore HoepttM 3459 Fifth Aw - Rtotarpv PenneylverVe 15213. Fetiruwy 19.1992. Hepatic angiosarcoma, or hemangioendotheliai sarcoma, is a rar tumor. Fewer than 200 cases have boon reported worldwide [1], and it is estimated that only about 25 cases occur each year in the United States [2]. These tumors are strongly associated with xposure to thorium dioxide [3] and gaseous vinyl chloride monomer during its polymerization to polyvinyl chloride [4]. Angiosarcoma may also be associated with radium [5], copper [6], anrfrogenic-anabolic steroids [7], oral contraceptives [8], and chronic idiopathic hemochromatosis [9-11]. Long-term arsenic exposure has been strongly implicated in the pathogenesis of hepatic angiosarcoma [12-19]. Findings in ail pre vious reports suggest that arsenic exposure was present for many years. However, to our knowledge, there have been no studies of how short-term arsenic ingestion relates to the development of this tumor. This report describes a patient with hepatic angiosarcoma that was associated with short-term ingestion of arsenic. CASI R5POPT A 45 year oid whits man. a steel production manager, was hospitalized with jaundice of two weeks' duration. He felt weM until low months prior to ad mission to the hospital, when be began to experience malaise and fatigue. Two weeks prior to admission, anorexia without weigit loss and a cough productive of Mood-tinged spuun developed. At age 12, ha had been treated for six months with arsenic (Fowler's solution. 7 tfrops a day) for `Saint Vitus' dance." Thirteen years talar, reamers basal ceil carcinomas developed and. over the following years, ware resected on many occasions. There was no history of exposure to thorium dioxide or vinyl chloride. Physical examination revealed spider angiomata and slight facial hyperpigmentation. There was no keratosis of the palms or solas. The liver span was 15 cm with a Arm and iiontender edge. The spleen was not palpable, and there was no evidence of ascites. There was dependent edema of the lower extremities. December 19S2 The Americas Jaamai ef MsMcWe Vekne73 933 UCC 080525 Results of laboratory studies showed a hemoglobin level of 15 g/dl. platelet court of 141.000/mm3, albumin level of 2.8 g/dl. total serum bilirubin level of 6.6 mg/dl, lactic de hydrogenase level of 1.023 lU/ltter (normal 60 to 200), al kaline phosphatase level of 497 lu/llter (normal 30 to 11S), SGOT level of 171 lU/liter (normal less than 41). SGPT 110 lU/llter (normal less than 45), and prothrombin time 14 sec onds (normal 10 seconds). Hepatitis-associated antigen and antibody were not found, and the alpha-fetoprotein level was not elevated. Sonography of the liver revealed diffuse, ir regular. increased echoes but no dilated bile ducts. Over the next two weeks, ascites developed and the pro thrombin time and biliru>in level increased further. On lapa roscopic examination, the liver appeared coarsely nodular needle biopsy disclosed hepatic angiosarcoma. Two weeks later, the patient complained of severe pan in the right i^per quattant and became lethargic. He died four weeks following hospital admission. At autopsy, the Uver. which weighed 2.010 g. was exten sively replaced by partiaJty necrotic and hemorrhagic tumor nodules. No tumor was found in other organs. Microscopic examination showed angiosarcoma cells along the liver sinusoids. Hepatic cell plates were encased into pseudogianouar rosettes by spindle-shaped neoplastic cells (Figure 1). The neoplastic ceils often coalesced to form spongy masses interspersed with cavernous blood-filled spaces. Reticulin fibers outlined collapsed vascular spaces within the more dense areas of the neoplasm. There was no cirrhosis. immunohistochemical examination with an antibody to factor VIll-related antigen [20.21] showed characteristic Tsnuar staining in me cytoplasm of the tumor ceils, as well as m normal vascular endothelium that lined some residual intact blood vessels. ^p/rtng rrt ^nasis wit This repor sarcoma; JJwLltdil jgrt duratic ^sted-Un tor on *0.24 g.TT (gwithera arsenicMostpati o*associ ports, sue *the ches reaepatiet small do: Theabst this pati ggnsistent trganerall The electron microscopic findings were consistent m the vascular endothelial origin of the turxx [22]. intact bma lamina outlined the vascular chamets of me neoplasm, and well formed intercellular tight junctions were identified. The luminal borders showed pmocytotic vesicles without ncroviili. The fingernails and liver tissue did not contain signifies** quantities of arsenic (10 fig or less per 100 g of tissue). COMMENTS Various liver diseases ranging from toxic hepatitis to cirrhosis have been reported in association with uticnc exposure to arsenic [12.23.24], Noncirrhotic portal hypertension has also been reported to occur in ex posed patients [25.26]. Arsenic is a known carcinogen most commcniv as sociated with basal cell and squamous cell carenonres of the skin [27.28]. In Roth's autopsy series m 27 vintners, malignancies had occurred in 16 and inciuttd three cases of angiosarcoma of the liver [12]. duration of arsenic exposure in these patients ran^ from 12 to 17 years with an estimated 53.7 g of arson* intake when calculated for a 12-year period [ 17 ]. 71* latency period from first exposure to arsenic until me development of hepatic angiosarcoma was 13 to 25 years. Regelson et ai. [ 17] in 1968 described a 49 year o man with psoriasis in whom hepatic angiosarcoma cirrhosis developed after treatment with Fowler's ^ lution for 17 years. The latency period was 24 y*** Subsequently, Lander et ai. [18] and Oaiderup at *" [19] each reported a case of hepatic angiosarcoma ^Urttilrec aiendoth jjwfrnrr hgic feat tftoride. L Anony Brl L Cm* por w 1 MKM of I 23: A Craec 15' l Rou of i PtlTW & T. Raw it: l- Mon g tr Bax D 10. Kw 11. Su ( 12. Ro- SSx DacawWai `9S2 Hi* immr.ean Journal ef Madleiiw Volum* 7' UCC 080526 ARSBOC-ASSOCIATOD t^ATC IWOKM ATOMS 1QAT CT U_ encasing at tiv^ , i by angtosan^ , >sm stain: ** consistent^ r [22]. Intact tag the neootesnuad ore identified, Tto ricles withc ^^^RngtagolonfftsisigsnwMoi M oxic hepatitis* lion with ctron* icirrhotic parti to occur in aw 4 commonly aw call carcinoma jy sarias in 27 16andindu*d livar [12]. TT satients rangto 3.7gofar sriod f 17]. Tt* manic until 9* i was 13 to 29 ida49 years* liosarcoma ard h Fowler * was 24 ye*rk many years altar long-term treatment of with arsenic-containing medications. ^liis report dsscnbesthstotrth case of hepatic an- ^g^coma associated with the medicinal ingestion of It differs from previous reports because of the 01 deration and relatively small amotsit of arsenic grated. Under a physician's supervision, arsenic was g!L tr.r only six months with an estimated total dose *024 9* The latency period was 33 years, which fails wgm w range of other estimates of the latency period wsen(conduced malignancies [27,29]. i^.t patients with either liver disease or maiignarvggg associated with arsenic ingestion also have skin Miens, such as keratosis and basal cell carcinomas at the cnest and back [30]. It is notable that some of jase catients with skin cancers took Fowler's solution n smail doses for only a few months [27]. The aosencs of measurable tissue levels of arsenic n mis patient 33 years after ingestion of arsenic is consistent with previous reports [12.17]. Although rttpnmteri in the tissues at the time of ingestion, arsenic S generally not detectable years after the patient has stopped ingesting it. Until recently, no dear distinction was made between mi endothelial and Kupffer cell origin of hepatic arv gxjsarcoma. Popper et al. [31] compared the pattxv logic features of hepatic angiosarcoma due to vinyl ehtonde, thorium dioxide, and arsenic and suggested t. Anonymous: Angiosarcoma or ts Her a powing pnston? SrMMJ 1981; 282:904-M8. _____ t Cantor for OisaaaaCanaotAngioearoomaotthatiw among 'oivwyvinivyti cwhsiawfiwda Mmwor*fTMtidr Miwsorw^p! .VMdy Roe 1974; 23:49-50. 1 MattMwnkg.lMPhyAXBaansfrfc6ndo9wllal caSwreoma ol ikwr following Thoratraatinfocaone. Am JPMM 1947; 23: 58S-811. f- Crooen x Jr. Johnson fcBt Anpo--coma of Bvar M aw manutecsae of polyvinyl cwonaa. J Occw> Mod 1974; Ifc 150-191. 1 Rosa jM: A com illuarating ttw affects of proiongad aoSan of radium, j Pom Boom932:3S: 89S-912.' 8- `"ninioi )T Manaiaa nfl <w mesons in rinayanl xnyara 3--auwMMoiogy 1977; 7 Z75-283. 7 -=nk m, Thomoo LB. Poppor M, et aL: Hagado angioooroomo M^MinargmeoMlc amcMa. Lmkm 1 1 Monroe PS. RldOMI RH. Siogier M. Bakor AL: Hspade angwareoma. Posada raiaMonatve to jong-tarm oral con- . ttaeoedvs kigaotion. JAMA 19S1:240: S4-S9. * Bafcar HC. Pegs* CM. Oavaon J: haamanQioandoeialloma of 0 liver. jPamoiBactahan95S;7X 173-18X w- Xwntkan j. Tartow LA: tiMmocnromatoaia and Kieffsr-cM sarcoma with unusual location of iron. J Pathol Bacterid . 195S: 92: 971-573. *t- Xaaman 6X Nydck L Xey OF: Komanpooutodwilal aarooma o( the (Ivor id A-"""--"---"-- Aroh Pathol Lad MM thet the tumors proOably were derived from endothelial cede. Subsequently, factor VIM. a known endothelial cell marker, was found in the tumor calls in tow cases of vinyl chloride-associated hepatic angiosarcoma [32], as wed as in a case of oral contraceptive-associated hepatic angiosarcoma [8], The positive immunoper111idea a staining of tills patient's neoplasm with a factor VIII antiserum supports the endothelial call origin of arienio-associatad hepatic angiosarcoma. The development of skin cancers and hepatic an giosarcoma in this patient, who had only a brief expomi to arsenic, suggests that tiiere may be no safe threshold of arsenic exposure, in view of the long la tency period and the previously widespread medicinal use of arsenicala, additional cases of arsentc-essociated hepatic angiosarcoma may yet occur. A careful history concerting even short-term or low doss i sxposwe in ail patients with hepatic angiosarci uncover more examples of this association. We wish to thank Or. Yang K. Kim and Or. Anthony M. Pkreilo, Director of Laboratories. Butler County Me morial Hospital, tor permission to we thee autopsy data and materials and Or. Swamddcan NaUtohamM tor re ferring the patient. We thank Or. Hans Fromm for Ms heipM review of ttie manuscript and Mts. Loretta MMIsy tor exoallant secretarial assistance. ix Oar MM MonSt 1987; X 172-17X F, Hager R, stale i '.Jl 1383-1388. ix ftennlia M, Met OA. dotMioma mMgnDSeMpMBy i MM CM 1871; 99:984-88X IX Mek Kft MnancfiyiiM Mias f w Svw. kc CMW K. aM rPtol Hy Oi WpBBBMHr OCWOTO, Wjw TOraZiMll Wttey and Sons, 1878:288-307. IX Fast H.HamattJT.BenondSl_ at aL: Review of fotreaaM ot cMktnM hapMe angioawcoma iiaiaaM anvfronmanM wnonic naposwe in one oase. Canonr 1981; 47: 382-381. 17. ot (her from Weenie wamc inmicMon by FowMr's solution. Cancer 1888:21:514-322. IX LaMar JJ. StanleyAASumnorHW.ataU/ wfSi Fowtsr's sOMton <p 1975; 98: 1582- t98X 19. DaMane LMi Freni SC. Sraa X BmnteUeaat FX Angtoaaroome of 9w ilvar in ttie Maiwrlanda. J Qcctp MM 1976; 1X444. 20. Starnowgar LA: Imnmocywdwmiaey. 2nd ad. New York: John Wiley and Sana, 1979:104-170. 21. fcUuik. Roam J. OuQdorf WHC: LocMadon of factor VMreiMM andQM in nMeular andodiailai cada using an in* imawparOMdMo nwdwd. Am J Swg FMM 19S0; 4: lit" Mi f ^ Human c, * ewcin(Mn, "tinomam. BRIEF REPORTS id A sojw * totfnev- x resorts or new clinical or laboratory observations, eases of c*reinom* l * Artec/* ( **** ** tmportairce. tuib new developments in medical ears will I' iWOWeftu rbr publication in this section. Manuscripts must ' trped eouole-spaced. Text length must not exceed ~-0 gax no more than 10 references and one ligure or cable can i M ,urg See 'Information for Authors" on page 1-6 for form of I jmnuirirr Manuscripts should include an abstract of not over I :jq words. Reports will be reviewed by consultants when, in 1 in 30OH<-nw J cr-nion of the editors, such review is needed. The Editor ' roes' -? :ne right to snorten reports and to make changes in J 1 u*ie. 'her inonii^ J ^"iw h>r r| j S I9T*.,a ' Mvlviiu Go, Tumors in Patients with Angiosarcoma of the Liver vOOLAS J. VIANNA. M.O.. NI.S.P.H. New Yorx State Department of Hearth. 3ureu of Environmental Eoidemioiogy ana Occupational Health: - oany. Now Yarn. am : osarcoma of the liver is an exceedingly rare vascu* Ur rumor chat has been associated with exposure to thori um aioxide. arsenic, and vinyl chloride monomer (1. 2). Using methods previously described (1). the Bureau of Occupational Health. New York State Health Depart ment. developed a registry of all histologically confirmed rases of angiosarcoma of the liver diagnosed in residents :t New York State from 1970 through 1975. Detailed medical, social, occupational, familial, and therapeutic intones on each patient were obtained from their closest siic .-cxatjves and physicians. Slides of all patients in* rrucca in the registry were reassessed blindly for diagnos* x accuracy by a panel of pathologists. All other slides *natmg to diagnoses of other malignancies in these pa* 'rents were also reassessed. Of the 26 patients included in the registry, six were found to have nine histologically confirmed additional primary neoplastic tumors. Table 1 indicates the proba ble types and duration of exposure for these six patients. . In general, persons with a first cancer are at 1.29 times increased risk overall or developing a new independent nonsimuiianeous primary cancer compared wuh persons who never had cancer (3). These findings may weil be fortuitous, and tne small number of patients (and person yearn involved limits the value of statistical analysis. However, the rarity of an* giosarcoma of the liver (annual incidence rates ranging from 0.14 per million [2] to 0.25 per million population) (1), the high frequency of other primary tumors ob* served, and the very short interval between the diagnosis of angiosarcoma of the liver and most of the other tumors observed (Patients 1 to 4. Table i) support the hypothesis that exposure to these three carcinogens might be of etio* logic importance m the pathogenesis of many of the dif ferent types of tumors observed in each patient. Morever, evaluation of the past medical, social, and therapeutic histones of the six patients did not suggest that other factors (such as smoking or radiation) could account for these observations. None of the pauems had a family his* tory of any of the tumors Listed in Table 1. Patient 1 had a sister in whom breast cancer was diagnosed: Patient 2 had a father in whom stomach cancer was diagnosed; and the father and mother of Patient 4 had diagnoses of Hodgkin's and myeloid leukemia, respectively. Several mortality studies (4, 5) have found a slight to moderate excess of digestive tract, lymphatic, urinary tract, and brain cancers among cohorts with occupational exposure to vinyl chloride. Other studies (6), however, have failed to document these results. Findings of experi- T*M l. Omenmwe Oa ot the Liver and Other Primary Malignancias Patient Sex Angiosarcoma of the Numoer Liver Patient Year Age at of Diagnosis Diagnosis Type Other Primary Malignancies Year of Diagnosis Probable Exposure History and Duration Year of Death yrs I F 40 M 22 M 6g *M 3F 6F 63 43 64 1965 1968 i<m 1973 1970 1973 Squamous ceil carcinoma, left ftnger Giant follicular lymphoma, breast .Adenocarcinoma, prostata Choiangiocarctnoin*. liver Lymphosarcoma, small intestine Transitions) ceil carcinoma, bladCar Transitional cell carcinoma, bladdar Meningioma, brain Ftbramysoiiposarcoma. knea 1963 1968 1968 1968 1935 1971 1973 1939 1969 Lived less than 1 mile from a vinyl chloride factory ( 13 years) Thorotrast* Unknown, chemist-teacher i l > ear) Unknown, cleaning and maintenance (40 years) Lived less than one mile from a vinyl chloride factory (22 years) Arsenical pesuetdes (43 years) 1963 1968 1968 1971 1973 1974 1975 UCC 080528 menu! studies have shown that this chemical induces adenoma, adenocarcinoma of the lung, brain tumors, lymphomas, and other tumors in venous animal spams (7). Arsenic :s generally accepted as a cause of Bowen's disease and probably certain respiratory tract cancers (8). Other neoplasms that have icss frequently been attributed to chronic arsenic exposure include cancers of bladder, prostate and liver and leukemias and lymphomas (8). Chronic exposure can produce lymphomas expenmental ly (9V Thonum dioxide has been associated with cancer of the maxillary unuses, meningioma, and bile duct and acute and chrome myeiogenaus leukemia (10). Further study of the possible spectrum of malignant disorders associated with exposure to each of the three agents cieariv is warranted. Because most patients with well-documented angiosarcoma of the liver have no doc umented exposure to any of these three chemicals (1), . some consideration should also be given to the possibility that other agents structurally similar to vinyl chloride (such as chloroprene. trichloroethylene) might play a role in the cause of this and possibly other maiignent disor ders. Rmwii tor rtsnnts mould he unmM to Nicholas J, Vienna, M.D.: Bureau of Environmental Eoiocraioiofy ano Occunational Health. Tower Buiiduif, Tha Governor Ntnon A. RoeafaUcr Empire Stale Plaza; Albany. ny IUULNCU 1. BsaOy J. UsaXATOat F. Haarts P. ai. Anpoaamoma of the liven an mdanuoioftt turvey. J Not! Cancer last. 1977;S*tl3*3-J. L. HiaTh CW la. Fauc H. Caaicx JL la. Characxsruaca of eases at infMwcoma oi the liver amonf vinyl chlorals worsen in the Unnad States. aoi) <VY Aden So. 1973:3440) IA 3. Iominmic BS. Muitiwwpnmary naomaams in tmnona ai bifli nak of sanew. In PaAVMa.Ni JF. ao. ao Appnoa m Cancer Enotogy tod Coamt. New Yont: Academic Praia. 1973:103-19. * Tacmsmaw JR. Samr WR. Mortality nudy ot worhen m tM mawuieerare oi vmyi eniondc and in menoman. J Oeeap Mod. 1974:14009II. 3. Waxwuls* RJ. STainoaa W. Waoons* JJC. at aL Naoplaene rak amonf warden aspoaed to vmyi chloride, aob NY Aeud So. I97fcJ71:4<M. Fox AJ. Cou.1I* PF. Morality caoenence of workan axooead to vinyl chionda monomer to the manuficnue of potyvmyt enkonoe m Gfaaa Bnlain. Br J Inamt Mod. I977:J4;1-I0. ViOLa PL. Bioeorn. CaATo A. Oncofcmc nmpon*4 of rat tktn. lunp and hone to vinvi chionoe. Conor Rot.1971;31:310-9 I. SCNOOLMturu WL. Whits DR. Aflame pcnonuif. South Mod J. I9ta73il9l-:0I. 9. SvnoUman FW Ja. a review of the caremofamcinas at nwkei. chnv mium ano motae compounds m man and anmuia. Pro* Mod. I97fcJii*9.94 10. MfVLIft L. Rodieoenro Itotopm to Sido EJFocts of Druf*. New York: Enema Meoica Foundation: 1960:441-9 3.9BI Amenean Coxefe at ft-yweiana Estrogen Receptor Activity in a Case of Hodgkin's Disease JAMES J. STahk. m JOHN w .lOvO. ?h.O.: ana PAUL SCHE,,HAMME=. M.2. Eastern Virginia Mecicai Senooi: Norfolk. Virginia. The qiscovery by Jensen and colleagues tl) And others (2) of the presence of estrogen receptors in human breast cancers and the subsequent correlation of the presence of hormone receptors and response to therapy have had profound effects on the modem management of patients with advanced cancer of the breast. Estrogen recept r 188 Avyuar : ft: Aan e- i-ta-nai Mve.eiA# VCyn ft mao