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THOROTRAST-INDUCED HEPATOMA Geoffrey L. Smoron, md,* and Hector A. Battifora, md* A case of thorotrast-induced hepatoma is presented. The patient was given Thorotrast intravenously, in 1943, for diagnostic x-ray studies. Autoradio graphic and electron microscopic studies confirm the diagnosis 28 years later. A review of the world's literature is tabulated. A short history of the use of thorotrast is given, and its carcinogenic potential is discussed. The question of chemical vs. radiation carcinogenesis remains unsettled. A plea is made for earlier diagnosis, so that an effective plan of treatment may be attempted. he occurrence of malignant tumors Physical examination was unremarkable ex Tfollowing the use of thorium dioxide cept for evident hepatomegaly, the liver edge suspension (Thorotrast) as a contrast agenbteing palpated 7 cm below the right eosul by radiologists has been well established in margin. the world literature, yet the number of cases reported in the United States has been few. The following report is, to our knowledge, only the tenth published case of liver car Laboratory studies were recorded as fol lows: hemoglobin, 11.2 g/100 ml; hematocrit, 33%; WBC, 14,300; LDH, 343 mp/ml; SCOT. 96 mp/ml; alkaline phosphatase, 244 mp/ml; total bilirubin, 0.6 mg/100 ml. cinoma in the United States associated with X-ray studies revealed large opaque densi the use of Thorotrast, although eight cases ties in the liver, spleen, and upper abdominal of hepatic hemangioendothelioma have also lymph nodes (Fig. 1). At this time, it was sus been reported. pected that the patient might have been given Thorotrast, in 1943, at the time of her chole Case Report cystectomy, and this was subsequently substan tiated. A liver scan (Fig. 2) reported a mass R.V., a 60-year-old Caucasian woman, was admitted to Chicago Wesley Memorial Hospi tal on October 1, 1971, with complaints of in termittent spasms of the left facial muscles, oc casional fever, chills, and mild upper abdomi nal distress. She denied alcoholism. Past history revealed hospitalizations for cholecystectomy in 1943, subtotal thyroidec tomy for hyperthyroidism in 1949 (hepatome galy was noted at this time), and medical eval uation of hypothyroidism at another hospital 2 months pnor to admission. Again, hepato megaly was noted, but no other abnormality was reported. defect in the right lobe corresponding to the opacity on x-ray, with markedly distorted and decreased activity in the left lobe. Tumor was suspected. A percutaneous liver biopsy done on October 12, 1971, revealed portal fibtosis and pigmentation in the Kupffer cells. An alpha fetoglobulin test was negative. On Octo ber 17, 1971, an open liver biopsy was per formed. Sections revealed a mixed hepatocel lular carcinoma (Fig. 3). The patient had a difficult postoperative course, but was finally discharged on November 18,1971. A course of chemotherapy was considered but was not given. R.V. was readmitted on January 5, 1972, in * Resident. Department of Therapeutic Radiology, Chicago Wesley Memorial Hospital. Chicago, 111. t Associate Professor of Pathology. Northwestern Uni versity Medical School; Chief of Surgical Pathology, poor general condition. She complained, of weakness and abdominal pain. On physical examination, the patient was jaundiced, as cites was present, and she was diagnosed as Chicago Wesley Memorial Hospital, Chicago. III. Address for reprints: C. L. Smoron. MD, Department of Therapeutic Radiology, Chicago Wesley Memorial Hospital. 2501 Superior St, Chicago. Iff. 60611. The authors are grateful to Dr. William T. Moss. being in liver failure. Abnormal laboratory findings were: hemo globin. 9.0 g/100 ml; hematocrit. 27%: WBC, 13,500; LDH, 646 mp/ml; SCOT, 422 mp/ml; Director of the Department of Therapeutic Radiology at Chicago Wedey Memorial Hospital, for his careful review and criticism of this paper. They also wish to t thank Joan Davis and Nicolina Litteria, who aided in alkaline phosphatase, 513 mp/ml; total biliruj CO bin, 13 mg/100 ml; blood urea nitrogen, cn mg/100 ml. 'the research and preparation of this manuscript. The hospital course was one of progressive Received for publication July 7,1972. coinfusion and lethaarrwgyv., and the opatient died 1252 oa Janu: topsycot Wedgt arotomy processei tions of mm? cut tureof c hvde bu Alter 2 post-fixe drated ; Class an on cop graphed scope ai ParaS ness we in the i sion N" sion-coa boxwii of livet rtable ex liver edge *ht costal td as folrmatocro. il; SCOT, 4 mu/mfc ]ue densihdotninal s susgiven her cbofcysubsun- ;-d a m ng to the orted and umorwas >psy done il fibrosis cells. An OnOaovas pervepatocelnt had a -as finally course of vas not , 1972. in lained of physiol diced, asjnosed as re: hetnoWBC 2 tnu/mt :al bilirurogen, 45 rogresnse ient died Fig. 1. AP (left) and lateral (right) x-rays of abdomen demonstrating Thorotrast deposits in liver, spleen, and abdominal lymph nodes. on January 30, 1972. Unfortunately, an au topsy could not be obtained. Materials and Methods Wedge biopsies of the liver obtained at lap arotomy were fixed in buffered formalin and processed by routine histologic methods. Por tions of the biopsies were minced into 1-2 mm5 cubes and fixed immediately in a mix ture of cold glutaraldehyde and paraformalde hyde buffered to pH 7.2 in phosphate buffer. After 2 hours, they were washed in buffer, post-fixed in 1% osmium tetroxide, dehy drated and embedded in epon epoxy resin. Class and diamond cut sections were mounted on copper grids and studied and "photo graphed with a Philips 300 electron micro scope at 75 kv. Paraffin-embedded sections, cut at 5 p thick ness were deparaffinized, hydrated, and coated in the dark with Kodak nuclear track emul sion NTBj for radioautography. The emul sion-coated slides were stored in a light-tight box with desiccant at 4C. Six weeks later, they ------------------------------ --------------------------------------- --------p- !K. t AP (top) and lateral (bottom) camera views f liver scan demonstrating suspected tumor. C CO oo 10 to**i < o z WlOW< 1254 Cancer November 1972 Vol# Fic. 3a. Phoiomiaograph of the fiver biopsy. There is <&. organization of the architcaure. fibrosis and fornution of r. generative nodules os the right. A focus of carcinoma cells is seen in the lover left corner. Collections of Thorotrasl-comaininj macrophages are sees in the center. Prolifer ating ductules are abundant (H and E. X50). Fic. 3b. Photomicro graph of tumor area. Note anastomosiug cords of anaplastic cells. A collection of Thorotrast-containiag macrophages occupies the left lower corner (H and E, X450). were developed and stained with hematoxylin and eosin. Morphological Findings Light microscopy (Fig. 3): The hepatic ar chitecture was severely distorted. Portal areas were widened by broad adjoining bands of connective tissue containing numerous chronic inflammatory cells and histiocytes. The latter, which often appeared in dusters, contained a variable amount of an amorphous crystalline material which was not birefringent or stainable. The hepatic lobules were markedly distorted, and nodules of regenerat ing liver cells of variable size were conspicu- W lO W < VoLJO ffutooio^ f the fin, there Is di$- -- ion of the ire, fibiosi, iau'on of ree nodules oo A focus of a cells is be loser left tbOectioos of st-coouioing 'go are sea iter. Prolifauctules are lH ud , Thorotrast-indlced Hepatoma Smoron and Batttfora 1255 ous. Around these regenerating nodules, there ere numerous proliferating ductules. Occajjonal atypia of hepatocy tes and ductule cells sere seen. One of the biopsies was almost entirely composed of neoplastic tissue. The tumor cells sere grouped in anastomosing cords and were sliglulT larger than normal hepatocytes. They had abundant, eosinophilic cytoplasm, round or oval nuclei with one or more eosinophilic nucleoli. Mitoses, often atypical, were numer ous. Electron microscopy of the tumor (Fig. 4): Abundant collagenous stroma containing macrophages and fibroblasts surrounded the nets of tumor cells. Electron-dense material. presumably Thorotrast, was seen within some of the macrophages. The tumor cells were characterized by irregular outlines, abundant endoplasmic reticulum, and mitochondria. Their nuclei had variable amounts of chroma tin and often multiple, sharply outlined nu cleoli. The most distinctive feature was the presence of biliary canaliculi between tumor cells. Microvilli and tight junctions, structures normally present in biliary canaliculi, were conspicuous in the tumor cells. Autoradiography (Fig. 5): Autoradiography disclosed numerous short, straight tracks ema nating in spoke-like fashion from the intracel lular crystalline material. The number of tracks was proportional to the amount of for- K)<m < 0 2 . PbotoniaO' tumor area, sastomosiog 5 aoaplasac coHectioQ of 2*coouiniog ges octopts lower corner W X450). numerous histiocytes, in clusters, imorphous t birrfrinrules were regenerat: conspire- Tic. f. Electron micrographs of representative tumor cells. "Hie nuclei have irrrgular out lines. satiable chromatin content, and large, multiple nucleoli. The arrow points toward a bilbrr canaliculus formed by three liver cells. The same canaliculus is shown in the inset sun an arrow pointing toward a tight junction. Macrophages containing lipid vacuoles and electron dense material, consistent with Thorotrast deposits arc present in the fibrous stroma (x&wP, inset X8J800). 1256 Cancer November 1972 VoL )o fie. 5. Autondio' graph showing charactrristic alpha (rads radiating from Thorotrast-containing ma;rophagcs (H and counterstain, x350). eign material present, the tracks being typical o{ those produced by alpha particles. Discussion The morphological features in the liver biopsy are typical of Thorotrast-induced liver cirrhosis and hepatoma. The autoradiographs confirm that the foreign material contained within macrophages and Kupffer cells is radioactive and compatible with Thorotrast depos its. The formation of canaliculi by the tumor cells indicates their origin from hepatocytes and a certain degree of differentiation, al though no morphological evidence of bile for mation was present. Thorium dioxide was first used experimen tally in 1915, for lacrimography by German researchers.51 It wasn't until 1928, that Blubaum et aL developed a thorium dioxide sol which was used in bronchography.1 In 1929, Oka found that when injected with Thoro trast, rabbits retained the contrast material in their spleens, and, in the following year, he showed that good visualization of both liver and spleen could be obtained in humans.* Af terwards, it was found that thorium dioxide could be of great use as a contrast agent in other parts of the body. Thorotrast, the improved thorium dioxide sol, was developed in Germany in 1950, and contained a 20% (by weight) colloidal solu tion of thorium dioxide.^ This was used widely throughout the world because it was an excel lent contrast material, supposedly with no se rious side effects. However, not everyone was convinced of the safety of this popular agent. W'eiser warned, as early as 1950, that, since Thoro trast was retained for long periods of time, in juries due to this material would not be recog nized for several years.81 In both 1952 and 1957, the Council on Pharmacy and Chemistry of the American Medical Association warned against possible hazards from use of Thorotrast, and the use of Thorotrast in the United States was restricted to patients with malignant tumors, advanced age, and to instances in which no other con trast agent was considered suitable.18-1* Several other countries issued similar warnings. As early as 1955, it was shown that Thoro trast could induce malignancies in rats, but most felt that this animal data could not be extrapolated to humans." Based on the ob served latent interval of about I year in rats, development of malignant tumors in man was predicted to have a latency of 12 to 15 years.1 Although a rase of acute leukemia was linked to the use of Thorotrast in 1942.** it jwasn't until 1947 that the first primary he- patic cancer was reported.4* Since that time, many types of malignancies have been attrib uted to the use of Thorotrast, but the most 1 frequently involved organ has been the liver. The most frequently reported histologic VolJt F,- 5. Autoradb. graph showing actcristic alpha ir*j, radiating from TW trast*containing rophages (H and E couniersuin, *350). m he world because it was an excelmaterial, supposedly with no seects. - * everyone was convinced ol his popular agent. \\'eiier arty as 1930, that, since Thoro. lined for long periods of time, inthis materia] would not be recog;ral years.*5 932 and 1937, the Council on id Chemistry of the American iciation warned against possible use of Thorotrast, and the use oi t the United States was restricted 'ith malignant tumors, advanced nstances in which no other conis considered suitable.1*-1* Several es issued similar warnings. 1933, it was shown that Thoronduce malignancies in rats, but t this animal data could not be to humans.*7 Based on the obinterval of about 1 year in rats, of malignant tumors in man was lave a latency of 12 to 15 yean.1 a case of acute leukemia was use of Thorotrast in UW2,** it 1947 that the first primary bewas reported.** Since that rime, f malignancies have been attribise of Thorotrast, but the most olved organ has been the liver, frequently reported histologic S'oi 5 Thorotrast-indl'ced Hepatoma Smoron and Batiifora Table 1. Hepatic Carcinomas and Sarcomas Histologic type Total no. of cases Percentage (male) Latency (yrs.) Average age (yrs.) Cholangioma Hepatoma Other carcinomas Sarcomas 40 65% 20.5 49 24 50% 22 53 18 70% 21 53 41 70% 22 55 Note: Detailed tables of cases reported in the world literature are available on request from 1257 type in the earlier literature was the heman- by ionizing radiation has long been estab gioendotheliosarcoma which has an average la lished, the occurrence of liver cancer in re tency of 22 years. In more recent yean, how- sponse to non-radioactive chemical poisoning eser, the number of carcinomas reported has raises serious doubts concerning the cancer-in hr exceeded the number of sarcomas reported ducing mechanism. in a ratio of 2:1. The reason for this is unex Both arsenic and thorium are known to pro plained, since the latency for the development duce liver cirrhosis, and the higher incidence of carcinoma, 21 years, is approximately the of hepatomas in cirrhotic livers is noted in same (Table 1). many textbooks. Yet, rapidly dividing cells are Thorium is principally an alpha emitter, known to be more sensitive to irradiation, and with an average penetration of only about 40 those in a regenerating liver may be more sus u`(%5). ceptible to malignant change through con The liver is known to take up over 70% of stant bombardment by radioactive particles. the injected material, where it is distributed The question remains unsettled. heterogeneously throughout the reticuloen The number of cases of liver malignancies dothelial system. Studies reveal the urinary ex due to Thorotrast has increased in recent action to be very slow, so that the biologic years, especially in Japan and the Scandina half-life is calculated to be over 400 years.5*" vian countries. No similar clear-cut trend' Determination of the radiation dose to the tis seems apparent in this country, however. It is sue, as with internally administered radioac not known if there is a lack in diagnosing or tive materials, is exceedingly difficult. Esti in reporting these tumors. mates of the average dose to the whole liver It is hoped that this paper will stimulate an vary from 1 to 9 rads/week, depending on the index of suspicion among clinicians so that given amount of Thorotrast. Although the av more of these people may be identified in the erage calculated dose to the liver is in the premalignant latent period, and a plan of range of 1,000-3,500 rads over about 20 years, effective therapy evolved. This might include some areas may receive only 700 rads, while hepatic lobectomy if Thorotrast deposits are other areas received as much as 15,000 rads localized. A few cures of juvenile hepatic he due to the non-uniform distribution.4*-71 mangioendotheliomas by surgery have been The mechanism by which Thorotrast in reported.11 For those lesions with multifocal duces cancer remains open to question. Sev origin, vigorous chemotherapy should be con eral papers describing a high incidence of sidered since the chances of affecting a small liver malignancies in cases of chronic arsenic number of tumor cells would be better than poisoning have been reported.*4-*7-** These the chances of reducing a large bulky lesion, have included both carcinomas and sarcomas. discovered late in the clinical course of the Although the induction of malignant tumors disease. REFERENCES l. Abo, M., et alj Case ot liver cancer caused by thonasL Jap. J Cancer Clin. 15:822-826.19GB. . ? 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