Document J2dQRg98Nw6rRkEb8zbz9qGO

Benzen( Exposure and Aplastic Anemia Followed by IJ Leukemia 15 Years Later Richard L. DeGozuin, M D , Chicago A painter who was exposed to benzene for 13 years developed a hypocellular bone marrow and pancytopenia. During the 15 years after recovery from aplastic anemia, there were found in the peripheral blood leukopenia, throml~ocytopenia, and anemia. Night sweats, petechiae, splenomegaly, and pancytopenia prompted examination of the marrow, which was found to he characteristic of acute inyelogenous leukemia. ATOM BOA4B VICTIMS have developed leukemia from 1 to 14 years, or longer, after exposure to irradiation.' M7ith such a long induction period, clues to the elusive cause of leukemia may disappear years before the disease becomes manifest. The prediction that mothers who deliver large babies will probably have diabetes mellitus later in life provides a valuable oppoltunity for studying diabetes without being led astray by the eflects of disturbed carbohydrate metabolism. Similarly, recognition that patients recovering from aplastic anemia may later develop leukemia gwes one a chance to observe the so-called preleukemic period.2-' Preleukemia should be carefully described to facilitate investigation of stem-cell regulation before tbe anarchic leukemia state supervenes. The patient whom we studied says that he was extensively esposed to benzene and later developed aplastic anemia; both conditions are associated with an increased risk of leukeniia.'-' Blood counts obtained during a 15-year period after recovery' from the aplastic anemia revealed a persistent hematopathy which finally emerged as subacute myelocytic leukemia. Report of a Case Aplastic Anemia.-The patient, a 41-year-old house painter, entered Hines Veterans Administration Hospital on Resident in Internal Medicine, Department of Medicine, University of Chicago, ncd Argonne Cancer Research Hospital (operated by the University of Chicago for the US Atomic Energy Commission). July 15, 1947, with complaints of anorexia, nausea, dark urine, light stools, fevers, and weakness for 1 week. As a house painter who worked inside, he had routinely thinned his paints with benzene for about 13 years. . - His blood pressure was 130/90 mm Hg, his pulse, 120 beats per min. The skin and conjunctivae were icteric. There was gingivitis. The spleen, liver, and kidneys were not enlarged, but right upper abdominal tenderness was present. Initial blood counts were: hemoglobin level, 14 gm/100 cc; red blood cell count, 4,98O,OOO/cu mm; and white blood cell count, 4,5OO/cu mm with 59% segmented neutrophils, 38% small lymphocytes, 2%. monocytes, and 1 % eosinophils (Fig 1). The urine was normal except that it contained bile. Direct serum bilirubin was 12.1 mg/100 CC, total bilirubin, 18.0 mg/100 cc. Alkaline phosphatase w a s 7.8 Bodansky units/100 cc. Icteric index was 101.2 units. Choline chloride, vitamin B comples, and thiamine were given, but there was only slight improvement, after which the patient began bleeding from his gums. Blood counts were not changed much, but 2 weeks later, on Aug 20, 1947, Lvlien the bleeding persisted, the hemoglobin level was 10 gm/100 cc; red blood cell count, 3,60O,OOO/cu mm; and white blood cell count, 1,3OO/cu mm, with 10% neutro- E'g 2.--. sect! 3f the s:..rnurn Lhils and 30'. BONE MARROW BIOPSY 4 EL000 TRANSFUSIONS 4J 'u' 9W 5 / I W 151 I<- V X I\ 'I t \' ' '01 I I'((I 1I \ -' 11'1 1948 50 ') 56 58 60 62 Fig 1 .- Hemoglobin, leukocyte, and platelet counts from 1947 through 1962. Shaded areas at top and bottom represent the ranger of normal hemoglobin and leukocyte values respectively. Key: Hemoglobin level (gm/lOO ccl solid line, leukocytes ( 1 O,OOO/cu mml dashed line, and platelets I 1 00,00O/cu mml dash-dot. 112 OI1185, No 10 1,- LEUKEMIA-DEGOWIN 749 JAMA, Sept 7, 1963 I* `r Y orexia, nausea, dark i s for 1 week. .is a s d routinely thinned m. Hg, his pulse, 120 :were icteric. There kidneys were not d e r n e s s was presin level, 14 gm/100 m; and white blood inented neutrophib, s, and 1 % eosinoaxcept that it con; 12.1 mg/100 CC, e phosphatase \\-as x was 101.2 unit`. and thiamine n w e ,merit, after which ims. Blood counts later, on Aug 20, hemoglobin level 3,600,000/cu mni; with 10% neutro- J d", "u' "\i unts from 1.947 )resent the ranger dively. Key: He( 1 0,00O/cu mm) i-dot. ig 2.-A section of bone marrow obtained by trephine biopsy f the sternum, on A u g 23, 1947, i s hypocellulor ( X 350). ihils and 90% lymphocytes. There were only 30,000 plateets/cu mm. A bone marro\v aspirate on Aug 21, 1947, \vas iypocellular. Defective maturation of both granulocytic and `rythrocytic series was evident. In the former: the number If myelocytes equaled that of metamye1oc)-tes and polynorphonuclear leukocytes; the pol~.chromenormoblast was he predominant cell in the latter. Few hlasts of any sort <ere seen. Xlegakaryocytes \\'ere scarce, but there were iumerous lymphocytes, plasma cells, and fat-containing macrophages. A trephine biopsy of the sternumi, obtained In Aug 23, 1947, revealed an estremely h,-pocellular marow (Fig 2 ) . T h e majority of cells occupying a few small oci of reticular proliferation were nongrnnular mononncears resembling large Iymphocytes and plasnia cells. A few solated groups of two to three normoblasts and granulo:ytes were present. No tubercles \\'ere found. Dr. George V. >eRoy, the hematological consultant, concluded that the latient had developed aplastic anemia after exposure to )enzene while convalescing from severe hepatocellular aundice. Consistent with Dr. LeRoy's recommendations, the paient was given 14 pints of whole blood during the nest 4 veeks. Extract of yellow bone marrow (one ampule daily) vas given intramuscularly for about 10 weeks. Penicillin, QOOO units every 3 hours, n'as given during the first week. 3leeding from the gums stopped after the 4 weeks of blood mnsfusions. A bone marrow aspirate on Oct 4, 1947, pro`ided evidence of early, but not too successful, marrow `egeneration, according to Dr. LeRoy's interpretation. No kucleated erythrocytic cells were seen in the hypocellular narrow: Lymphocytes and mononuclear cells described as he "monocytoid leukocytes of Donney" were predominant. kspite !ow blood counts, the patient seemed sufficiently `ecovered to be discharged on Dec 31, 1947. `Subsequently the patient \vas given liver and iron injecions and examined periodically in the outpatient departbent. H e felt well and had no recurrence of bleeding. Hemoglobin values reached the lowest limit of normal, but mild leukopenia was constant. Anemia and leukopenia were still present on the last blood counts obtained at Hines Hospital on June 16, ,1949 (hcmoglobin level 13.0 g m / l O O cc, white blood cell count 4,OOO/cu m m ) . Prelcttkanic Period- No more blood counts were avail- able until 1956, when the patient came to the University " of Chicago Clinics complaining of belching and lower ab- . domina1 cramps. Except for a scar over his sternum and a grade 1/6 apical systolic murmur, his examination was normal. Anemia and mild thrombocytopenia were prescnt. During the--next 4 years, while the patient was treated with a bland diet and phenobarbital for an irritable COIOU,a persistent anemia was apparent from periodic blood counts. One neutrophilic myelocyte, two metamyelocytes, and normoblasts were reported on the peripheral blood film on Jan 23, 1960. The bleeding time from an ear puncture ex- tended beyond 15 minutes. On Feb 9, 1960, the day of the patient's first University of Chicago Hospitals admission, the liver was palpable two finger-breadths below the right ribs, --.`b u t the spleen was not palpable. The left ear was red and swollen. Anemia, thrombocytopenia, and leukocytosis were present. No immature cells were seen on several blood film . examinations while the patient was in the hospital. In- creased mature granulocytes accounted for the elevated myeloid-erythroid ratio noted on the section of bone m a m ~ aspirate obtained on Feb 11, 19GO. Cellularity, maturation, megakaryocytes, and stained iron were all noma1 (Fig 3 ) . . After his discharge, the patient returned to work every day as a drill-press operator. H e scemed healthy, but ad- mitted that he bruised \vith slight trauma and that spon- taneous bruising occurred. Routine blood counts on hlarch 4, 1961, demonstrated leukopenia and anemia. Fourteen months later, a personal physician told the patient that he was severely anemic and recommended that he return to the University of Chicago Hospitals. Fig 3.-A section of sternol bone morrow obtained by needle biopsy, on Feb 1 1 , 1960, shows normal cellulor mifuration ond megakoryocyter I X 3501. 113 li2 - . . '.. I 750 LEUKEhlIA-DEGO WIN I JAMA, Sept 7, 1 9 Q Leukemia-On his second admission, May 17, 1962, the patient told of, recent nose bleeds, and ecchymoses were /j The hematologists considered subacute myelogenous leu.; kemia the most likely diagnosis. I! found on his arms, chest, and legs. The heart was slightly The patient returned to his work, taking 30 mg of p e d i ' enlarged. The spleen was firm 3 cm below the left ribs. A nisone daily. He experienced easy bruising and more fre] nontender, firm liver extended 10 cm below the right ribs. Initial blood counts were: hemoglobin level, 7.4 gm/100 cc; dquent night sweats, and on July 27, 1962, the discovery o recurrent anemia (hemoglobin level 7.4 gm/100 cc) a n , hematocrit level, 24%; red blood cell count, 2,19O,OOO/cu mm; and white blood cell count, 2,70O/cu mm, with 31% segmented neutrophils, 53% lymphocytes, 3% monocytes, 6% myeloblasts, L% promyelocytes, 5 % neutrophilic mye- locytes, and -1% metamyelocytes. There were 7 normoblasts per 100 leukocytes. Subsequent counts: reticulocytes, 5.7% red blood cells/cu mm; and platelets, 15,4OO/cu mm. Sections of bone marrow aspirate obtained on May 22, 1962, contained hypercellular marrow in which the myeloiderythruid ratio was increased 10 to 1. Arrest of maturation in the myeloid series was evident from the predominance of myeloblasts and promyelocytes and a paucity of metamyelocytes and segmented neutrophils. Normoblasts were present. Megakaryocytes were rare. Prussian blue stained iron unas abundant. A serum protein electroghorectic pattern was dc- void of evidence of protein abnormality, including a "myeloma spike." A gastric aspirate contained hydrochloric acid. Plasma iron was 110 ~ g / 1 0 0cc; unsaturated iron binding capacity was 150 Pg/lOO cc. Plasma clearance of FeJ9 was about twice as rapid as normal. Ninety per cent of the in- jected radioiron appeared in the erythrocytes in 3 days, in contrast to a normal range of GO% to 70% in 7 days. Uric acid (enzymatic method) was 6.4-mg/lOO cc. Type A hemoglobin was detected by electrophoresis. The patient was afebrile, and except for several days of bleeding from his sternal puncture, he felt moderately well. He received 3 units of blood, and because of thrombocytopenia and probable hemolytic anemia, 30 mg of prednisone daily was begun several days before he left the hospital. Ithrombocytopenia ( 6,000 platelets/cu mm) prompted re. admission to the hospital. Immature cells were seen in th peripheral blood. Petechiae were present in the skin an mucus membranes. The spleen -was palpable 5 cm belo! athe costal margin, and the liver extended 6 cm below thr right, ribs. Sternal bone marrow aspiration was performed on July_.30, 1962, and sections were prepared. Sheets o immature cells with pale-staining nuclei resembling th myeloblasts of the previous sections occupied 90% of th mkeamrriocwhi(aFtuigs).4 )N.orNmoobmlaasttusreweleruekodcimytiensishweedr,e .asneden m(elegua. kkaryocytes were rarely found: The marrow was unquestion ably leukemic. The patient was transfused with 3 units.0 blood and discharged with a diagnosis of ,acute myeIogenou 1leukemia. Blood counts in the outpatient department hav shown persistent anemia and thrombocytopenia. The patient got along fairly well taking prednisone untilf January, 1963, when leukocytosis nnging from 95,000. t.1 7146,000 leukocytes per cu mm (mostly myelocytes myeloblasts) occurred. There was transient impfovement Iwhile the patient took mercaptopurine. However, he died' on April 24, 1963, with a gram-negative bacterial pneu- monia and septicemia despite treatment with antibiotics, mercaptopurine, prednisone, 'and blood transfusiom. . Comment [ Extensive 'exposure to benzene preceded a per-[ sistent hematological abnoimality starting with, as. far as we know, a hypocellular bone marrow and pnaonrmcyatlopbeonniae wmhaircrhowwawsithfolvloawrieadblebyleuakonpeeanrilay,!I, . ' i , : . ' ! I . yaneaerms,iaa, faranndklythlreoumkbeomciyctompaernrioaw. aFnindapllayn,cyatfotepren1ia5[tf Fig 4.-A section of sternal bone marrow. obtained b y needle biopsy, on July 30, 1962, i s frankly leukemic. Sheets o f myeloblasts reploce normal marrow cells except for some normoblasts I X 3751. \\'ere found. It is tempting to relate the blood dis-1 eases, or disease, to benzene exposure. fof Benzene chronic bpeonizseonneingexpisosnuorte,Ga nbuitn, vwarhiaebnleposiesoqnuienlga'I, severe^has occurred, the bone niarrow varies from hypoplasia to extreme hyperplasia.' The first signs of poisoning may appear with an infection, long after exposure has ~ t o p p e dO. ~ur patient's hepatitis may have resulted from either benzene or a virus. Acute leukemia has occurred after benzene poi- soning in several instances; '-' one patient died with acute leukemia after 23 years of exposure to benzene.' Furthermore, leukemia has developed ir patients who have previously had hypocellu!ar bone marrow."'* ' The duration of a preleukemic phase in our p a tient cannot be determined because no blood counts are available from June, 1949, to Januaiy 1956. From 1956 until May, 1962, when the diag- nosis of leukemia was made, his course was char. acteristic of preleukemia as Block and others have described it." There was evidence of a lieniorrhagic ,tendency, and thrombocytopenia was present wher platelets were measured. Leukopenia and anemia were also present, dthough not always siniultane. ously. In describing a patient who developed leu. 114 LEUKEMIA-DEGOWIN .\ - 751 nyelogenous 14 kemia 9 years after the beginning of a prolonged cerning the manner in which the delicate control ;30 mg of prc ig and more f the discovery ;m/100 cc) k n) prompted were seen in 1 in the skin a ble 5 cm bel, 6 cm below t I was peiform pared. Sheets resembling t lied 90% of t were seen (le lied, and me$ was unquestic with 3 units ute myelogeno lepartment ha )enia. prednisone un from 95,000 myelocytes a lit improveme wever, he di bacterial pne vith antibiotic isfusions. %cededa pe rting with, ' marrow a1 by a near hematological disorder, Williams observed an initially hypocellular marrow; a preleukemic period characterized by anemia, neutropenia, and throm- bocytopenia, and finally, the subsequent development of a hyperplastic marrow and myeloblastic leukemia.' Although the maximal risk of leukemia occurred 4 to 7 years after the atomic explosion in apan, the incidence of leukemia was decidedly increased in exposed persons 14 years after the blast,' a latent period similar to that described in this study. The leukemia rate in Japan ordinarily is 20 to 30 cases per million people each year. The 1958 leukemia rate in persons exposed within a 1,500 meter radius of the blasts in Hiroshima and Nagasaki exceeded 450 cases per million.' '* If benzene poisoning caused this patient's blood disease, one might speculate a t great length con- of stem cell proliferation and maturation was perverted. As recognition of the preleukemic phase becomes more assured, the study of stem cell kinetics during that period will undoubtedly prove more rewarding than are present attempts to identify the cause of a leukemia during its end stages. 950 E 59th St, Chicago 37. Dr. ClifTord W. Gurney helped in studying the patient; Drs. Stanley Yachnin and George V. LeRoy offered suggestions concerning the patient's treatment; Dr. Armand Littman provided the patient's old records. This study was supported in part by a US Public Health Service fellowship from the National Heart Institute. Generic and Trade Names of Drugs Choline chloride-Choline Chbride. Prednisone-Deltasone, Deltra, Metacorten, Paracort. References . Brill, A.; Tomonoga, M.; and Heyssel, R.: Leukemia h4an Following Exposure to Ionizing Radiation: Sumry of Findings in Hiroshima and Nagasaki and Comparison with other Human Experience, Ann Intern Med 56:590, 2. Block, Al.; Jacobson, L. 0.; and Bethard, W. F.: Preleukemic Acute Human Leukemla, IAAfA 152:1018, 1953. 3. Beyers, M. R., et al: Hypocellular Marrow in Acute . Leukemia, Arch Intern Afed (Chicago) 88:803, 1951. 4. Aclams, E. B.: Aplastic Anemia, Review of TwentySeven Cases, Lancet 1:G57, 1951. 5. Hunter, F. T.: Chronic Exposure to Benzene (Benzol): 11. Clinical Effects, J Industr Hyg 21:331, 1939. 6. Rejsek, K., and Rejskova, M.: Long Term Observation of Chronic Benzene Poisoning, Acta Med Scand 152:71, 1955. 7. Mallory, T. B.; Gall, E. A.; and Brickley, W. J.: Chronic Exposure to Benzene (Benzol). 111. Pathologic Re- sults, ] Industr Hyg 21:355, 1939. 8. Erf, L. A., and Rhodes, C. P.: Hematological Effects of Benzene (Benzol) Poisoning, I Industr Hyg 21:421, 1939. 9. Williams, M. J.: hlyeloblastic Leukemia Preceded by Prolonged Hematologic Disorder, Blood 10:502, 1955. I leukopeni illy, after I pancytopeiil he blood di >. `able seque; en poisonin from sevei he first sigr fection, Ion nt's hepatiti le or a viru: benzene poi patient diel exposure tl developed ii zellular boni P .R E V E N T I V E HYGLENE SUGGESTIONS O F 1915.-But w e have not yet even begun to d e m a n d that study and care of t h e individual which is . . fundamental. \Ve have as yet paid little or no attention to over-eating, over-working, over-drinking, deficient exercise, deficient sleeping, family hygiene, and the hygiene of special organs, such as eyes, ears, bowels, nose and feet, all of which I propose to group together under the term preventive hygiene. We have achieved m u c h in preventive medicine and preventive sanitation, but we have as yet failed for the most part in preventive hygiene, which is perhaps the most important of all. Here, therefore, w e may reasonably expect the greatest progress in the nearest future. Rightly studied, preventive hygiene will include personal, domestic, family and social hygiene. I t will deal with celibacy and marriage, with housekeeping, with the high cost of living, with food economy, with domestic service, with child hygiene, a n d with the right conduct of mature and elderly life, as well as with personal hygiene. It will in the future play, perhaps, the principal part in solving many of e in our pa 3 no bloot to January -n the diag e was char others havc lemorrhagit resent wher and anemis simultane eloped leu 114 -1 the problems of American life, health, prosperity and happiness. Our teaching of physiology, both on the higher levels and the lower, has never emphasized as much as it should have done its practical hygiene applications to the conduct of life. In fact, our whole teaching of hygiene and sanitation has been grossly neglected. Even the best medical schools have paid b u t scant attention to these subjects, while the instruction given in our public schools has generally suffered from half-in- formed teachers a n d uninformed school committees. The best teaching of today is to be found, not i n the text-books or the schools, b u t in the leaflets and booklets of certain boards of health and life insurance companies. This, surely, is a scholastic reproach which must not be allowed to stand.-Sedgwick, W. T.: American Achievements a n d American Failures in Public Health Work, Science, July-Dec, 1915. -. -2