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New England Tournal of Medicine Y Established in 1812 a6 The NEW ENGLAND JOURNAL O F XEDICINE AND SURGERT VnT.TTM-F- , 271 - O C T O B E R 22, 1964 NUMBER 17 .-. e nerai Hospital Anemla and Valvular Heart Disease 898 J . P . de 1'. Hendrtckse, IY. P. Cockshott, K.T E. Evans and C. J . Barton C:!rbohvdrate Metabolism in Prepnancy. 1'. T h e Interrelations of Glucose, Insulin and Free . .. . .Fatty Acids in Late parturn P.reg.na.ncy. a.nd. p.ost. 866 Sheldon J . Bleichcr, John B. O'Sulltvan and Norbert Freinkel ll'illzam Datiiesliel, and Sanford I . R o t h -_. . . Editorials . ."Sex Information and Education Council" 906 .. ."Varium et Slutabile Semper Femina" . .. . . .Metropolitan Gets out the Vote 907 907 . . . . . . ..A Hospital is a Hospital . 907 . . . . . . . . . .i .Benzene and Leukemia . . 872 Massachusetts Medical Society 908 Enrico C. T'tgltani and Giulio SaltQ Reversal of Digitalis Intoxication by Beta-Adre- . . . .. . . . .nergic Blockade with Pronethalol . 877 Massachusetts Department of Unalth .... Public , 908 j= 2.R, Taylor, C . I . Johnston and G1- Anthony D. Jose Correspondence Special Article . . . .Evaluation of Lymphangiography 908 p?. Laurence B. E U ~ J Medical Progress 6 .. . .es,"?- Abdominal Surgery ( T o be concluded) 885 Claude E. Welch .. . .. ...-. Medical Intelligence !-:Current Concepts: Treatment of Ulcerative CO- ::, . . . . . . . . . . .. . .litis 891 5.. LOU^ Zetzel suppression 01 u p Training for Gene] Osteolytic vs. Oste Hypertension in FL -_____.-_..__ .Trishydroxy hIethyl Amino Methane ( T h a t IS) 911 . . .. . . . .Granby Coppers , -Autopsies Anotl , . . .Logomachy 912 . . . .. .Training for General l r a c n c e . . . . .. . . . . . .Scleral Icterus . YIL 913 @k' .. s. :~dou~opouloKs,. Kehayoglou, s. Stamatelopoulos and D. Sideru Notices . . . . . . . , . . . . . . xxx \ ir Owned and Published by The Massachusetts Medical Society Second-Class postage paid at Boston, Mass. and at additional mailing Published weekly at 8 Fenway, Boston, 02215. Domestic, I `11;i! ; 872 THE NEW ENGLAND JOUR unaltered disposition of glucose despite concurrent elevations of plasma insulin are interpreted as consistent with peripheral resistance to insulin during late pregnancy. Contrainsulin factor or factors of a lipolytic nature have been implicated. The metabolic interactions are designated as a form of "accelerated starvation," and the parasitization of maternal glucose and gluconeogenic precursors by the concep- tus is emphasized. It is postulated that the contributions from contra- insulin factors would be additive to the effects of intraplacental insulin degradation in the gestational challenges to maternal insulin economy. 15. 1G. 17. 18. 19. 20. 21. 22. 23, 24. We are indebted to Miss Carolann D'Amico for technical assistance and to Miss Claire Mahan for assistance in the statistical evaluation of the data. 25. 26. REFERENCES I. Freinkel, N. and Goodner, C. J. Insulin metabolism and pregnancy. Arch.'Int. M c d . 109:235-244, 1962. 2. Kyle, G. C. Diabetes and pregnancy. A n n . I n t . M r d . 59:l-82, 1963. 3. Freinkel. N., and Goodner, C. J. Carbohydrate metabolism in pregnancv. I. Metabolisni of insulin by human placental tissue. J. Clin. In&rtigation 39:116-131, 1960. 4. Goodner, C. J. and Freinkel, N. Carbohydrate metabolism in pregnancy: degridation of insulin by ertracts of maternal and fetal structures in pregnant rat. Endocrinology 6 5 :957-967, 1959. 5 . Idem. Carbohydrate metabolism in pregnancy. IV. Studies on permeability of rat placenta to I-131-insulin. Diabrtcs 10 :383-392, 1961. 6. Idem. Carbohydrate metabolism in pregnancy: turnover of I-131-insulin in pregnant rat. Endocrinology 67 :862-872, 1960. 7. Freinkel, N. Effect of pregnancy on insulin homeostasis. Diabetes 13:260-267, 1964. 8. Johnson, D. G., and Bonsnes, R. W. Intravenous glucose tolerance test in or . e ena I n c v..~ 7. Clin. Inurstieation 27:745-748. 1948. 9. Silverstone, F. A., Solomons, E., and Rubricius, J. Rapid intra- venous slucose tolerance test in pregnancy. J. Clin. Inuestigation 40:2180-2189. 1961. 10. 11. 12. 13. 27. 28. Van Duyne. C. M . , and Havel, R. J. Plasma unester acid concentration in fetal and neonatal life. Proc. SOC. E B i d . B .\fed. 102:599-602, 1959. 29. Roth, J . , Glick, S. M.. Yalow, R: S., and Berson, S. A. glycemia: potent stimulus to secretion of growth hormone. 1403987: 1963. 30. Unger. R. H., Eisentraut. A. M.,and Madison, L. L. total stamation upon levels of circulatins g!ucagon and man. J. Clin. Inuesfigotion 4 2 : 1031-1039, 1963. 31. Jorimovich. J. B., and .\lacI.aren, J. A. Presence in human and term serum of highly lactogenic substance immun related to pituitary growth hormone. Endocrinology 71 1962. 32. Kaplan, S. L., and Grumbach. M . M. Studies of h simian placental hormone with growth hormone-like and like activities. J. Clin. Endocrinol. 24:EO-100, 1964. 33. 34. tion 43: 1283, 1964. 14. me remainder \yere s)e,rythremia (2 c m). In all cases in 4 severe exposure tc 5 leukemia \\`as h e m ded bz- 2. period of a1 rdope:. ;a. In the province of bene p;isoning arOS lin;ng benzene in the i mmanufactured in IT &n also at workers' h phonal Health of the blast three Years 41 rom factories wl \yell above the ma: BENZENE AND LEUKEMIA* ENRICOC. VIGLIANI, M.D.,? AND GIULIO SAITA, M.D.$ MILAN, ITALY ..._ YPOREGENERATIVE and aplastic types of a case of leukemia referred to the action hemopathy brought about by exposure to ben- zene.' zene were described in the nineteenth century, and A paper by Cronkite2 (1961) summarizes tprofessor of industrial medicine, University of Milan. fMember, Institute of Occupational Health, Clinica del Lavoro. fore, we thought that it would be of some int give a short account of the cases of leukemia BENZENE AND LEUKEMIA -VIGLIANI AND SAITA 873 n of. lted to benzene in Italy, with special emphasis on fioSe Seen at the Clinica del Lavoro of the Universi- of Milan. In 1938 Penati and Viglian? reviewed the avail- ,ble world literature on benzene myelopathy and +nted out that, in some cases, the pathology hardly tore cut the diagnosis of aplastic myelosis - that is, welplastic bone marrow and leukemoid reaction. Although all types of leukemia have been attrib- uted to benzene, many cases reported between 1928 Ind 1938 lack reliable data on exposure to benzene. Physical examination showed pallor, a n enlarged liver and a spleen palpable 2 fingerbreadths below the left costal margin. Examination of the blood revealed a red-cell count of 1,410.000. with a hemoglobin of 34 per cent (Sahli), and a white-cell count of 4800, with 19 per cent hemocytoblast forms (including many microhemocytoblast forms), and occasional neutrophilic myeloblast forms, promyelocytes and myelocytes. T h e platelet count was 56.000. Sternal-marrow puncture yielded 71 per cent hemocytoblast forms, of which 36 per cent were microhemocytob!ast forms. No improvement occurred in spite of treatment. Hemor- rhages, fever and leukocytosis (white-cell count of 34,300, with 50 per cent heniocytoblast forms) supervened, and death followed after l!h months. Since 1941, 13 cases of "benzene leukemia" have CASE 2 . t I n 1940 R.F., a 38-year-old man, became a n reported in Italy, besides the cases of the Cli- assistant operator in a rotogravure firm, where the inks con- Lavoro of Milan and the Institute of OCCUHealth of Pavia, which will be considered tained 40 per cent benzene. The benzene concentration in the department where he worked varied between 0.60 and 2.10 mg. per liter. Asthenia and pallor developed in 1944. He had pain in the bones, with fever, i n 1945, when he these 13 cases, 9 were hemocytoblastic (or mye- entered the Clinica with pallor, slight splenomegaly and some ecchymoses and petechiae. bblastic, according to Naegeli's terminology) in type. T h e red-cell count was 1.450.000, with a hemoglobin of remainder were chronic myeloid leukemia (1 , erythremia (2 cases) and erythroleukemia (1 . In all cases in which a history of prolonged 38 per cent (Sahli), and the white-cell count 3700, with 9 per cent hemocytoblast forms and some immature mye- locytes; the platelet count was 50.000. T h e red-cell count fell to 800,000, and the white-cell count to 2200, with 33 severe exposure to benzene could be obtained, ukemia was hemocytoblastic in type, often pre:&d by a period of apparently aplastic anemia with per cent hemocytoblast forms. mostly micro forms. The spleen enlarged to the transverse umbilical line. and there were diffuse hemorrhages. The patient died in May, 1945. Post-mortem findings were myeloid (hemocytoblastic) meta- plasia of the liver and spleen: the sternal. costal and verte- bral bone marrow was atrophic. Other cases of benzene rovince of Pavia many cases of chronic anemia and a case of leukemia (Case 4) occurred in the isoning arose from the use of glues con- same factory. ene in the manufacturing of shoes. Shoes CASE 3. T.S.. a 29-year-old man. for 8 years was a spray many small factories, and very varnisher with nitrocellulose varnishes dissolved in solvents homes. The Institute of Occuhe University of Pavia saw in last three years 41 cases of chronic benzene in- containing 60 per cent benzene. I n 1956 he began to complain of asthenia and loss of appetite. I n July. 1958, high fever and diffuse pain in the bones developed. Our diagnosis was hemocytoblastic leukemia with leukopenia. Remission th hemopathy. Five of them were leuore precisely, 3 hemocytoblastic, 1 ic and 1 myeloblastic. All these cases followed treatment with cortisone. I n November. 1958, his condition appeared fairly good: the spleen was scarcely palpable; the red-cell count was 4,800.000, with a hemoglobin of 90 per cent (Sahli), and the white-cell count 47,800, tories where cases of aplastic anemia nd where the glues contained a high Pcentage of benzene. According to the determi- ations of benzene vapor carried out in some fac- $, workers with glue were exposed to concentra- bns well above the maximum allowable value. with 5 per cent hemocytoblast forfns and numerous neutrophilic myelocytes and metamyelocytes ; the platelet count was 150,000. Sternal-marrow puncture revealed a high concentration of hemohistioblast and hemocytoblast forms. On treatment with 6-mercaptopurine and prednisone the white-cell count fell to 3600, with a few myelocytes and metamyelocytes. Cessation of antimetabolites was followed in a short time by a rise in the count to 200,000, with 64 per cent hemocytoblast forms, which could be controlled by CASES SEENAT THE CLINICADEL LAVORO renewed treatment with 6-mercaptopurine. T h e patient was discharged in a satisfactory condition with a good hemato- -poietic response, a normal white-cell count and very few hemocytoblast forms. He was then lost to follow-up study. n. resent the clinical and laboraton, details of &6 cases of leukemia. l.* M.G.,a 49-year-old man, entered a leather- tory in 1933 as a spreader and calender operator, resins dissolved in benzene and acetone. Working s were bad, and many workers had fallen ill with After 1 year the patient complained of asthenia lor, with mucosanguineous diarrhea, a n d from 1938 , he had repeated epistaxis. His condition worsened, was admitted to our department in January, 1942. CASE 4. At 24 w a r s of aee. in 1938. M.A. beean to work in the same rotogravure department as Case 5 I n 1945, when his mate, R.F., died from benzene leukemia and other workers also had siens of benzene uoisonine. this man was not examined. Du&g 1949 he showed a-slight tendency to leukopenia (count of 4000) and relative neutropenia (count of 50 per cent). After 1949 benzene was replaced by toluene, xylene, hexane and organic acetates, and no further cases of benzene poisoning have since been found. I n the course of routine examinations M.A. was seen every 3 months and was reported normal until February, 1961, when he began to complain of asthenia, sporadic bouts of fever and pallor. I n March the red-cell count was 1,600.000, with a hemoqlohin of 29 per cent (Sahli), and the whitecell count 30,000, with 81 per cent hemocytoblast forms, mainly of the micro type. Sternal-marrow puncture gave evi- 'h'hiO'Jsly reported by Vigliani and Saita.' tPreviously reported by Saita.6 874 T H E N E W ENGL-IND JOURNAL OF 1IEDICINE Vol. 271 No. 1 dence of morphologically similar cells of hemocytoblastic type, with rare occurrence of granuloblastic and erythroblastic types. T h e platciet count was 83,000; the coagulation time (Howell method) was prolonged, and prothrombin utilization was markedly reduced. Transfusion. prednisone and 6-mercaptopurine led to marked improvement; by May, 1961, the red-cell count was -k:200.000w.ith a hemoxlobin of 80 per cent (Sahli). and the \\,hite-cell count 10.000, with rare hemocytoblast forms ( 3 per cent), neutrophilic myelocytes a n d metamyelocytes. Examination in February, 1962 (over a year after discharge from the hospital), after a relapse, showed a red-cell count of 2,000,000, with a hemoglobin of 30 per cent (Sahli): and a white-cell count of 83,000. with 58 per cent hemocytoblast forms and very few platelets. The patient had hemorrhagic and feverish bouts. Treatment with antibiotic transfusions, prednisone and 50 mg. of 6-mercaptopurine per day led to another transitory remission (white-cell count of 4000, with 32 per cent hemocytoblast forms), but fever reappeared, with bronchopneumonic foci a t the lung bases and a rise in the white-cell count to 63,000, with 57 per cent hemocytoblast forms, many of which were very atypical. At no time w a s either splenomegaly or lymphadenopathy disco\-ered. Death occurred in April, 1962. more than 1 year airer the clinical appearance of the disease. No autopsy \vas performed. CASE 5. M A . , a 50-year-old man, from 1943 to the spring of 1962 had a job of sticking rubber ribbons io the edge of billiards with glue containing pure benzene. spread on the ribbons with a pencil. H e did this work for 2 or 3 hours a day. .4fter the spring of 1962 the benzene in the glue was replaced with a nonaromatic solvent. In l-overnber, 1961. he experienced fever, asthenia a n d pallor; in June examination of the blood in a town hospital showed a red-cell count of 2,650,000, with a hemoglobin of 50 per cent (Sahli), and a u.hite-cell count of 2000, \vith 20 per cent neutrophils and 80 per cent mononuclear leukocytes : sternal-marrow puncture disclosed many atypical heniocytoblast forms and very few normal cells of the red and white series. He improved considerably with blood transfusions and corticosteroids and was discharged in good condition. .i checkup a t the Clinica del Lavoro in January. 1963. showed a rcd-cell count of 3.900.000. with a hemoslobin of 83 per cent (Sahli), and a white-cell count of 3900: with 1 2 per cent neutrophils, 4 per cent eosinophils, 48 per cent lymphocytes and 6 per cent monocytes; the platelet count was 60,000. Sternal-marrow puncture showed a normal bone marrow, with only a slight increase of basophilic erythroblast forms. During that winter the white-cell count fell progressively to 2500, and the neutrophils to 14 per cent, but no immature forms were seen in the circulating blood. .4t the beginning of March bouts of fever appeared: and the count fell to 600. with 15 per cent hemocytoblast forms, 1 per cent myeloblast forms, 5 per cent neutrophils. 78 per cent lymphocytes and 1 per cent monocytes. Sternal-marrow puncture disclosed very few cells. mostly of the hemocytoblast type. Corticosteroid treatment was started; the white- cell count remained between 1600 and 2400, a n d the hemocytoblast forms in the blood smear between 5 and 32 per cent, with no other immature form. Platelets diminished to the positivity of vascular fragility tests; the red-cell count was 2,800,000, and the hemoglobin 60 per cent (Sahli). At the end of April the patient went home and was lost sight of. At no time was enlargement of the spleen or lymph nodes noticed. CASE 6. L.A., a 53-year-old woman, was an artificialflower maker for 3 years, usins a glue dissolved in a solvent containing 25 per cent benzene. I n June, 1963. she had weakness, nausea and pallor. On admission to our department, examination of the blood showed a red-cell count of 1,800.000, with a hemoglobin of 40 per cent (Sahli): and a white-cell count of 2800, with 30 per cent neutrophils, 2 per cent eosinophils, 65 per cent lymphocytes and 3 per cent monorytes. with no pathologic cells: there were 16 erythroblast forms for every 100 white cells. T h e platelet count was 110,000. Sternal-marrow puncture gave a normal pattern except for a high number of mitoses. This hypoplastic anemia was treated with repeated blood transfusions. I n October there were attacks of fever, with a maxim temperature of 102.2"F. (39C.). On October 20 the w h z - cell count \\'as 51,000, with 4 per cent hemocytoblast and 8 per cent myeloblast forms, 14 per cent myelocytes, 4 per cent metan?yelocyles, 29 per cent neutrophils, 2 per cent eosinophils, 1 per cent basophils, 13 per cent lymphocyte3 and 25 per cent monocytes. T h e hemocytoblast and myelo; blast forms showed atypical features, with large cytoplasm and monocytoid nucleus. A total of 3 normoblast f o m , for every 100 white cells were seen. Sternal-marrow puncture performed on October 24 showed that almost the marrow were hemocytoblast and myeloblast faolrlmcse. lls'.:in- The patient's condition deteriorated rapidly in spite therapy with 6-mercaptopurine and prednisone, and she died on October 28 with large pharyngeal and buccal ulcers. T h e spleen was never palpable. Autopsy demonstrated complete leukemic metaplasia of the spleen, with leukemic infiltrations of the liver, lymph nodes. kidneys. colon, lungs and brain. T h e leukemic cells looked like undifferentiated stem' cells. DISCUSSION .. The attribution of the cases seen at the Clinics del La\.oro to the exposure to benzene cannot be doubted. Cases 2 and 4 occurred in the same workshop. and both patients ivere exposed to concentrations of benzene ten times greater than the maximum allo\\.abIe values generally accepted. I n Cases 1, 2 and 4:\vhich occurred in factories \vhere other workers !\.ere affected, aplastic or hyporegenerative hemopathy developed. Cases 3 and 6 handled a diluent containing a dangerous percentaze of benzene. Case 5 handled a glue dissohyed in pure benzene. The folloiving significant points are worth emphasis: Hematologically. the 6 cases described were similar. They \\.ere all hemocytoblastic leukemias with, sometimes, absence of ele\*ated white-cell counts, moderate or absent splenomegaly, thrombocyto-. penia and invasion of the bone marrow by intei:' sive hemocytoblastic proliferation. Thus, the pic-. ture was one of undifferentiated stem-cell leuke. mia, with myeloid characteristics as shown, for example, by a positive peroxidase reaction. Leukemias of this kind, even a few years zd,.ran an acute or a subacute course, with, at mo% a feiv weeks' survival. The terminal septic hemorrhagic phenomena today can be prevented by medicinal means so that fairly long remis ' ha!-e been obtained in some cases. I t is kno\rn that microhemocytoblastic le mias are especially sensitive to the folic a$dantagonists, to antimetabolites and to cortisone,:a. fact that may explain the longer and more fr?;. quent remissions of infantile leukemia in whi$ microhemocytoblast forms are more preva! than in adult cases. O n the other hand, cytoblastic leukemia ivith extremely large or ical cells is less responsive to these them measures. Cases 3 and 4 sho1ved many mi mocytoblast cells, ivith few atypical or larg cells. I n Case 4 the latter appeared in large D bers only in the terminal stages. Case 6 rapid course, probably owing to the highly a aspect of tb and paraniye monocyroid c Five of th at the outset apy. In Cast throughout, F leukopenia m finding leads mia ma!- not hemoc!-roblast terminal phas. I n Case 6 1 hypore,menelat also occurred Occuparional described in 1963. It is pc kemia develo anemia. Thus. Case 3r and spor3c s\.o years. C: bone n ? m ~ o ~ -I had xiild lei years before th The partici: the onset of a prencoplastic, better underst' carried out re' .:'xes oi huma of which had : cells obtained the mitoses bl of colchicine. Somes of 342 cent of rhe cell The large me two groups of (lence oi delet few cells. So chromosomal c Some D: or ci merary chromc tagenetic eff ec and may help mia during th anemia. -4ctua especially the an abnormal 1 and perhaps IT study of the cells in chroni. clinically and f tered chromosc We have ne or lymphatic 2 benzene: all u ol. 271 No. 17 BENZENE AND LEUKEMI.4 \,-IGLIANI AND SAITA 875 --s with a m& sober 20 the white. 'iemocytoblast q d myelocytes, 4 per Jphils, 2 per ccPl cent lymphoq.to toblast and myel6 h large cytoplm rmoblast fomr Io, I-marrow p u n c h almost all celh ,& loblast forms. .p apidly in spite-,, isone, and she din and buccal ulccn ipsy demonstrati; e m , with leukemj dneys. colon, l u g .ke undifferentiah > - .. -I at the Clinic izene cannot b L the same work ed to concentE nn the masimur '. I n Cases 1, here other worl enerative hem01 indled a dilue, of benzene. Ca nzene. 2 worth emphasi scribed were sir .c leukemias wit \vhite-cell coun ily, thrombocyl marrow by inte I. Thus, the p i stem-cell leu] as shown, for action. a few years a! 3e, with, at m( :minal septic 'a can be preven ~y long remislc -? xytoblastic leu :o the folic a nd to cortisone rer and more vkemia in Wh more preal ther hand, h: wly large or a' these therape' ed many micq iical or large-SI .ired in 1arge.F 2s. Case 6 ha avt l e highly I, -A aspect of the hemocytoblast (parahemocytoblast and paramyeloblast) forms, with an abundance of monocytoid cells in the circulating blood. Five of the patients had low lvhite-cell counts at the outset that lvere independent of any ther- apy. I n Cases 2 and 5 leukopenia was a feature throughout, and we consider it probable that the leukopenia may have escaped US in Case 4. This finding leads us to think that leukopenic leukeinia may not be an infrequent feature of benzene hemocytoblastic leukemias, leukocytosis being the terminal phase in many cases. In Case 6 benzene leukemia was preceded by a hyporegenerative or aplastic phase. Such an event also occurred in some cases seen at the Institut of Occupational Health in Pavia and in the case described in the United States by De Goivin6 in 1963. I t is possible that many more cases of leukemia developed on a background of aplastic anemia. Thus, Case 1 complained for eight years of pallor and sporadic epistasis. Case 3 ivas asthenic for t 1.0 years. Case 2 sho1ved diffuse atrophy of the 1me niarroiv (sternal. costal and vertebral). Case 4 had mild leukopenia and neutropenia for twelve years before the late appearance of the leukemia. The particular aspect of these cases. in which the onset of a frank leukemia \vas preceded by a preneoplastic, hyporegenerative phase, may be better understood i n the light of an investigation carried out recently by Pollini and Colonibi' in 6 cases of human aplastic anemia due to benzene, 1 cf trhich had a fatal outcome. They cultiyated the cclls obtained by sternal puncture, and observed the mitoses blocked in the metaphase by means of colchicine. Then they mapped the chromosomes of 342 dividing cells and saw that 70 per cent of the cells showed abnormalities in karyotype. The large metacentric chromosomes of the first two groups of the Denver classification gave evidence of deletions; polyploidism was limited to a few cells. Some other cells showed structural chromosomal changes, as the presence of a chromosome D, or chromosomal fragments, or supernumerary chromosomes. This finding suggests a mutagenetic effect of benzene on the blood cells, and may help to esplain the appearance of leukemia during the course of a benzene hypoplastic anemia. Actually, it is known that leukemic cells, especially the most undifferentiated, often possess an abnormal karyotype. I t would be interesting, and perhaps rewarding, to undertake a systematic study of the chromosomes of the bone-marrow cells in chronic benzene poisoning and to follow clinically and hematologically the patients with altered chromosome pattern. We have never seen a case of chronic myeloid or lymphatic leukemia in workers poisoned with benzene: all cases seen by us and at the Institute of Pavia, in rvhich harmful and prolonged exposure to benzene vapors was ascertained, were heniocytoblastic in type. Whether chronic types of leukemia can be induced by benzene is still an open question, but Tve must emphasize our view that in some of these cases reported in the literature the occupational history was not convincing. The number of persons occasionally exposed to benzene or esposed to very low benzene concentrations was so high that some cases of chronic leukemia could have occurred among them as among any other working population. JVe are fully aware of the fact that no final statement about the existence of a true "benzene leukemia" may be made, without a statistical analysis of the incidence of leukemia among workers exposed to benzene as compared with that among a control group of the same age, sex and lk-ing habits. Unfortunately, this analysis is particularly difficult in our cases because of the large number of shoe and other factories handling benzene. the artisan Tvork carried out at home by many factory-employed ivorkers and the frequent and unsuspected changes in benzene content of the glues and solvents used by the Tvorkers. In the biennial period 1959-1961 the incidence of all forms of leukemia among the general population of llilan was 0.01 per cent; 46 per cent of these were acute leukemias, 28 per cent chronic myeloid leukemias and 26 per cent chronic lymphatic leukemias. Thus, each year 1 case of acute leukemia occurred among 20,000 people. There is reason to believe that in the Milan and Pavia provinces no more than 5000 workers irere exposed to contact \rith benzene and probably less than 3000 were exposed to dangerous concentrations of benzene vapors. According to the statistics of the National Institute for Insurance against Accidents and Occupational Diseases from January, 1960, to December, 1963, cases of blood dyscrasias due to chronic benzene poisoning occurred in the provinces of Milan and Pavia as shown in Table 1. The incidence of acute leukemias in 1962-63 showed a sharp rise, coinciding with the increase enzene i n t o x i c m TABLE 1. B!ood Dyscrarias D u e to Chronic Benzene Poisoning in the Prouinces of Milan and Pavia, 1960-1963. YLAR N O . OF NO.OF CASES DUTHS 1960 1961 1962 1963 Totals 4 7 36 -21 68 1 2 I1 -' 12 26 ANEMIA NO. OF CASES 4 6 31 NO. OF DEATHS 1 I 7 LEUKCVIA KO. OF CASES 0 1 5 NO. OF DEATHS 0 1 4 876 THE NET\' ENGLAND JOURNAL OF MEDICINE IlO!. 2 : even assuming that 5000 people \\'ere exposed t -e 6-mercaptopurine and showed remissions. These .-.>, & -9- G z e n e . Moreover, if one considers the cases of 1.orable responses to modern therapy may have beGzc=*e andzbenzene poisoning that actually occurred, 11 due to the presence of microhemocytoblast f o m s I#3* cases of le&emia among 68 of blood dyscrasias can- to the scarcity of atypical cells: in the patient whaz: RE not be overlooked. The incidence of leukemia is even more striking if one considers the fatal cases: out of'26 deaths, 11 were due to leukemia, and 15 to aplastic anemia. Our figures correspond fairly well to those collected in France by Cavignauxs; according to him, during 1960-61, 42 cases of benzene myelopathy occurred, 25 in men and 17 in women; 6 of these 42 cases were leukemias. From 1947 to 1961, 45 fatal cases of chronic benzene poisoning were recorded in France; 15 patients had acute leukemia, 22 aplastic anemia, and 2 lymphatic and 6 myeloid leukemia. These data point out the high incidence of leukemias among the cases of benzene poisoning in France and the prominent position of acute stem-cell leukemias among the cases of leukemia attributed to benzene. I t may be interesting to compare the action of benzene and of ionizing radiation in producing leukemia : they seem to stand in contrasting position in that the former more readily causes the acute hemocytoblastic type, and the latter the chronic myeloid type. died rapidly in spite of the therapy, the hemo,-yt,& blaAstttceenltlisoInreries gcroasllselyd attyopitchael. initial Ak : leukopenia ----w%r -I .-% m-&benzene leukosis and the frequency of hyporegenera..11= tive or aplastic stages before the development frank leukemia. In 1 of the 6 cases, the leukemia appeared !.ears after cessation of the exposure to benzene. A summing up of the cases of benzene athy seen at the Institute of Occupational of Pavia and in France shows approximate same incidence of leukemias (12 to 15 per seen at our institute and the high prevalence cell (hemocytoblastic and myeloblastic) types. Leukemia. mainly hemocytoblastic or mye tic in type, may be due to the action of be Great caution must be e w cised before admitting ben7ene etiology of chronic m)eloid or lymphatic t\ pes of leukemia. :;T rhythm the p" talis is layed E either i plerion The ?stem goups, vasocon 'e! carc ripherai blockad s\r?-atl We are indebted to Dr Maurice I V . Goldblatt, who ttanslatpd the Italian manuscript into English and helped prt jlng prc :ere1 Our Case 4, ivith a latent period of t\relve years after cessation of exposure to benzene. does not permit us to attribute the disease to persistence of lis with suqqestions and criticisms. and to Professor Salvatore llaugeri director of the Institute of Occupational Health of the University of Pawa. who gave us information about the cases of benzene myelopathv seen at his institute. mimals di!italis For c h i benzene in the bone marrow. A similar case, with md mc a latent period of fifteen years, was recently pre- REFERENCES ias beer sented by De O n the basis of the initia- tion-promotion theory of the induction of neo- plasms, ive might regard benzene as an initiator of the leukemia process, but we have no sug- gestion of a possible promoter. Hyporegenerative and pancytopenic types of he- mopathy are more frequently associated with ben- zene than the hyperplastic-anaplastic types. The cases of hypoplastic hemopathy are almost always reversible. I n our series of 31 cases of in- volutional myelopathy, only 2 were fatal, and 1 of these from complicating typhoid. Leukosis, on the other hand, is always fatal. We suspect that, for- merly, many fatal cases diagnosed as acute or sub- acute hemorrhagic aleukia were really cases of acute leukopenic or aleukemic leukemias. SUhlMARY AND CONCLUSIONS In the last twenty years 47 cases of benzene hemopathy have been seen at the Clinica del Lavoro of Milan; 40 were hypoplastic in type, and 2 of them were fatal. Six were hemocytoblastic leukemia. No case of chronic typical myeloid or lymphatic leukemia was seen. Two of the 6 cases of leukemia, seen in 1942-45, were rapidly fatal. Three of the remainder, seen recently, were treated with corticosteroids and with 1. Dclorc. P.. and Dorgomano, C. LcucGxnic aigue au coun d e.: . 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