Published data on Japanese leukemia patients with a preleukemic hematological disorder were assessed. The reexamined cases were from the &#34;Japona Centra Revuo Medicina&#34; reported during the period from 1952 to 1971. Among preleukemic hematological disorders, hypoplastic anemia was the most frequently reported (41 of 62 cases). These &#34;hypoplastic preleukemia&#34; patients were rather elderly and terminated mostly in atypical myelocytic leukemia. The chief hematological feature of the hypoplastic preleukemia cases was the coexistence of a relative erythroid hyperplasia and a slight increase of myeloblasts in the bone marrow that was unusual in hypoplastic anemia. The presence of pancytopenia and hypocellular marrow with a relative erythroid hyperplasia combined with a slight increase of myeloblasts probably indicates hypoplastic preleukemia that terminates later in acute leukemia.</p

Hiraki, Kiyoshi

Kitajima, Koichi

Mikochi, Hiroshi

Nakanishi, Toshio

Sakato, Junya

Takahashi, Isao

English

Okayama University Digital Information Repository

Preleukemia: hematological disorders prior to onset of leukemia

Okayama University Scientific Achievement Repository

Acta Medica OkayamaVolume 29, Issue 6 1975 Article 6DECEMBER 1975Preleukemia: hematological disorders prior toonset of leukemiaIsao Takahashi∗ Toshio Nakanishi† Junya Sakato‡Hiroshi Mikochi∗∗ Koichi Kitajima†† Kiyoshi Hiraki‡‡∗Okayama University,†Okayama University,‡Okayama University,∗∗Okayama University,††Okayama University,‡‡Okayama University,Copyright c©1999 OKAYAMA UNIVERSITY MEDICAL SCHOOL. All rights reserved.Preleukemia: hematological disorders prior toonset of leukemia∗Isao Takahashi, Toshio Nakanishi, Junya Sakato, Hiroshi Mikochi, KoichiKitajima, and Kiyoshi HirakiAbstractPublished data on Japanese leukemia patients with a preleukemic hematological disorder wereassessed. The reexamined cases were from the “Japona Centra Revuo Medicina” reported duringthe period from 1952 to 1971. Among preleukemic hematological disorders, hypoplastic anemiawas the most frequently reported (41 of 62 cases). These ”hypoplastic preleukemia” patients wererather elderly and terminated mostly in atypical myelocytic leukemia. The chief hematologicalfeature of the hypoplastic preleukemia cases was the coexistence of a relative erythroid hyper-plasia and a slight increase of myeloblasts in the bone marrow that was unusual in hypoplasticanemia. The presence of pancytopenia and hypocellular marrow with a relative erythroid hyper-plasia combined with a slight increase of myeloblasts probably indicates hypoplastic preleukemiathat terminates later in acute leukemia.∗PMID: 132844 [PubMed - indexed for MEDLINE] Copyright c©OKAYAMA UNIVERSITYMEDICAL SCHOOLActa Merl. Okayama 29, 437-444 (1975)PRELEUKEMIA: HEMATOLOGICAL DISORDERSPRIOR TO ONSET OF LEUKEMIAIsao TAKAHASHI, Toshio NAKANISHI, junya SAKATO, Hiroshi MIKOCHI,Koichi KITAJIMA and Kiyoshi HIRAKIOkayama University Medical School, Second Department of Internal Medicine,Okayama 700, Japan (Director: Prof. Kiyoshi Hiraki)Receivedfor publication, July 25, 1975Abstract: Published data on Japanese leukemia patients with apreleukemic hematological disorder were assessed. The reexaminedcases were from the" Japona Centra Revuo Medicina" reported duringthe period from 1952 to 1971. Among preleukemic hematological dis-orders, hypoplastic anemia was the most frequently reported (41 of 62cases). These "hypoplastic preleukemia" patients were rather elderlyand terminated mostly in atypical myelocytic leukemia. The chiefhematological feature of the hypoplastic preleukemia cases was thecoexistence of a relative erythroid hyperplasia and a slight increase ofmye10blasts in the bone marrow that was unusual in hypoplastic ane-mia. The presence of pancytopenia and hypocellular marrow witha relative erythroid hyperplasia combined with a slight increase ofmye10blasts probably indicates hypoplastic preleukemia that termi-nates later in acute leukemia.The terms "preleukemia" and "preleukemic stage" have been appliedto hematological disorders prior to the onset of leukemia. Experimentally,hypoplastic anemia-like hematological findings, such as pancytopenia andhypocellular marrow, have been observed frequently in murine leukemias in-duced by chemicals, irradiation and viruses (1, 2, 3). Since the report ofBlock, jacobson and Bethard (4) in 1953, many reports on this subject havebeen published. Hypoplastic anemia, sideroblastic anemia and a few otherhematological disorders have been confused with the preleukemic stage (5, 6,7,8,9. 10, 11, 12, 13, 14).In japan, clinical investigations of the preleukemic stage have been con-ducted systematically with atomic bomb survivors (15, 16). In many cases,no leukemogenetic agents, such as irradiation or chemicals, have been identi-fied. What sorts of hematological changes are present most frequently in thesecases? Are there hematological and clinical characteristics in leukemia witha preleukemic stage? The present paper examines the types, incidences andsome selected clinical data on leukemia cases with a preleukemic stage in thejapanese literature.4371Takahashi et al.: Preleukemia: hematological disorders prior to onset of leukemiaProduced by The Berkeley Electronic Press, 1975438 I. TAKAHASHI, T. NAKANISHI, J. SAKATO, H. MIKOCHI, K. KITAJIMA and K. HIRAKIMATERIALS AND METHODSA total of 62 cases of leukemia with a preleukemic stage were collectedfrom the"Japona Centra Revuo Medicina." These cases were reported in Japanduring the period from 1952 to 1971. The reports were collected under thetitle of preleukemic stage, abnormal hematological changes prior to the devel-opment of leukemia (17). Cases of atomic bomb casualties and congenitalhematological diseases were excluded. Clinical and hematological studies wereperformed by the reporting investigators. They were particularly detailed incases of hypoplastic preleukemic stage. The term .. hypoplastic preleukemicstage" was applied to cases of hypoplastic anemia which terminated later inleukemia.RESULTSPreleukemic hematological disorders and their incidencesVarious preleukemic hematogical disorders were reported (Table I). Theclinical diagnosis of hypoplastic anemia was most frequent (41 of 62 cases,66.1 %). Preleukemic reports of erythropoiesis disturbances including sidero-blastic anemia and pernicious anemia were present in eight cases, and myelo-proliferative disorders, such as myelofibrosis and polycythemia vera, werefound in six cases.TABLE 1. REPORTED CASES OF LEUKEMIA WITH A PRELEUKEMIC HEMATOLOGICALDISORDER IN JAPAN FROM 1952-1971NumberHypoplastic anemiaSideroblastic anemiaHyperchromic megaloblastic anemiaRefractory normoblastic anemiaAchrestic anemiaPernicious anemiaPolycythemia veraPolycythemia-MyelofibrosisMyelofibrosisBanti's syndromeOthersTotal41121132132562Sex and age distributions of cases with a preleukemic stageThe male-to-female ratio in 58 cases (4 unknown cases excluded) was36 : 22. The age distribution of the sample is shown in Fig. I.2Acta Medica Okayama, Vol. 29 [1975], Iss. 6, Art. 6http://escholarship.lib.okayama-u.ac.jp/amo/vol29/iss6/6Preleukemia 43940302010Leukemic cases(N=4 09)----",,,,,,,,1 - 19 40 - ,,9 60 -A'JeFig. 1. Aged distribution of preleukemic cases. Theleukemic sample was from our clinic.Leukemia cases from our clinic were used as controls. The preleukemicstage tended to be more frequently in cases of the fourth or fifth decade oflife. In 39 cases with a hypoplastic preleukemic stage (2 unknown casesexcluded), the male-to-female ratio was 25 : 14. Of 41 cases, 22 cases (53.6%)were above the fourth decade of life.Duration of preleukemic staJ~I..'_So. 01 casesSurvival artl'r diaHllo . .;is 0" leukemia\0. ot cases15 10 2 1 1 2 10 IS·1M1M 3M3M 6M6"1 9"1__-, ~M 1Y _II' 2Y21' 3Y3Y 41'41' SY51'Fig. 2. The clinical course of preleukemic cases._ , Hypoplastic preleukemic casesCJ, Other preleukemic casesM, month; Y, year3Takahashi et al.: Preleukemia: hematological disorders prior to onset of leukemiaProduced by The Berkeley Electronic Press, 1975440 I. TAKAHASHI, T. NAKANISHI, J. SAKATO, H. MIKOCHI, K. KITAJIMA and K. HIRAKIClinical course of leukemia with a preleukemic stageThe duration of the preleukemic stage and survival time after the estab-lishment of leukemia diagnosis are summarized in Fig. 2. The duration andsurvival time were too variable for defiQitive conclusions. It can be said thatthe preleukemic hematological changes tended to be short once the diagnosisof leukemia was established. This tendency was also present in cases witha hypoplastic preleukemic stage.Types of leukemia with a preleukemic stageThe types of leukemia in the 57 cases (5 unknown cases excluded) with apreleukemic stage are listed in Table 2. Fifty-one cases were diagnosed asacute leukemia (31 acute myelocytic leukemia, 7 monocytic leukemia, 5 acutelymphocytic leukemia, 2 erythroleukemia and 6 unknown types). Thirty-sevenof these 51 cases (72.6%) passed through a hypoplastic preleukemic stage.This suggests a close relationship between acute leukemia and a hypoplasticpreleukemic stage.TABLE 2. TYPES OF LEUKEMIA WITH HYPOPLASTIC PRELEUKEMIC STAGETypes of leukemia Total casesAcute leukemiaAcute myelocytic leukemia 31Monocytic leukemia 7Erythroleukemia 2Acute lymphocytic leukemia 5U~M~ 6Chronic leukemiaChronic myelocytic leukemia 6Chronic lymphocytic leukemia 0Unknown 5Cases with hypoplasticpreleukemic stage225235oo4Hematological characteristics of cases with hypoplastic preleukemic stageAll 41 cases with a hypoplastic preleukemic stage underwent some treat-ment for hypoplastic anemia. Some authors indicated reservations on thediagnosis of hypoplastic anemia. These cases had evidence of monocytosis,reticulocytosis and the appearance of erythroblasts, immature cells and un-differentiated cells in peripheral blood and a relative erythroid hyperplasia,a slight increase of myeloblasts, a shift to the left of the granulocyte seriesand the appearance of undifferentiated cells in the bone marrow. The in-cidences of these hematological findings in 16 cases in which detailed datawere available are listed in Table 3. Three major features were present inhigh frequency: the appearance of erythroblasts in peripheral blood (68.8%),4Acta Medica Okayama, Vol. 29 [1975], Iss. 6, Art. 6http://escholarship.lib.okayama-u.ac.jp/amo/vol29/iss6/6Preleukemia 441the slight increase of myeloblasts (68.8%) and a relative erythroid hyperplasiain the bone marrow (81.3%). Two of these features, a relative erythroidhyperplasia and a slight increase of myeloblasts, were present simultaneouslyin 10 of 16 cases (62.5%). These 16 cases terminated in acute leukemia. Atthe time of leukemia diagnosis about 60% of cases were aleukemic-hypo-cellular, and blasts were found at low percentage (less than 10% in the peri-pheral blood) in 7 of 16 cases (43.7%) (Table 4).TABLE 3. ATYPICAL HEMATOLOGICAL FINDINGS IN 16 CASES OF CLINICALLY DIAGNOSEDLEUKEMIA WITH A HYPOPLASTIC PRELEUKEMIC STAGEHematological findingsPeripheral bloodMonocytosisReticulocytosisPlasmocyte (+)Immature cell of granulocyte series (+)Erythroblast (+)Undifferentiated cell (+)Bone marrowRelative erythroid hyperplasiaSlight increase of myeloblastLeft shift of granulocyte seriesMonocytosisPlasmocytosisUndifferentiated cell (+)No. of casesI61211313113114TABLE 4. HEMATOLOGICAL FINDINGS AT DIAGNOSIS OF LEUKEMIA IN 16 CASES WITHA HYPOPLASTIC PRELEUKEMIC STAGEHematological findingsPeripheral bloodNormal or decreased WBCLow percentage of blasts (below 10%)Bone marrowDecreased NCC (below 70,000)Low percentage of blasts (below 20%)No. of cases1078/13 cases4/14 casesDISCUSSIONThis investigation showed that the hypoplastic preleukemic stage wasthe most frequently reported preleukemic hematological disorder in Japanduring the period from 1951 to 1971. It is uncertain whether a hypoplasticor hypocellular marrow was present before the onset of leukemia. Hiraki andIrino (1) and Soda (2) reported that the hypoplastic marrow preceded anabrupt increase of leukemic cells in 20-methyl-cholanthrene-induced and5Takahashi et al.: Preleukemia: hematological disorders prior to onset of leukemiaProduced by The Berkeley Electronic Press, 1975442 I. TAKAHASHI, T. NAKANISHI, J. SAKATO, H. MIKOCHI, K. KITAJIMA and K. HIRAKIradiation-induced murine leukemia. Furthermore, they reported hypoplasiaof the bone marrow at the preleukemic stage in tissue cultures of bone marrowcells. We have also observed this phenomenon at the preleukemic stage inBALB/c mice inoculated with Rauscher leukemia virus. From these data, wecan postulate that the hypoplastic anemia-like hematological findings precedethe onset of human leukemia.It may be important clinically to differentiate the hypoplastic preleuke-mic stage from the so-called hypoplastic anemia in patients with pancytopeniaand hypoplastic marrow. In hematological examinations of 86 cases withidiopathic hypoplastic anemia admitted to our clinic in the past 20 years, anumber of atypical hematological findings were determined. These atypicalfindings in hypoplastic anemia corresponded to the unusual hematologicalfindings detected in the 41 reported cases of hypoplastic preleukemic stage.Among these atypical findings, the coexistence of a relative erythroid hyper-plasia and a slight increase of myeloblasts in the bone marrow was observedin a high percentage of hypoplastic preleukemic cases. This coexistence wasseldom found in hypoplastic anemia (18). It may, therefore, be a usefulclue in the diagnosis of the hypoplastic preleukemic stage.It is interesting to determine whether all types of leukemia have apreleukemic stage. Acute leukemia was found in 51 of 57 cases with a pre-leukemic stage. Thirty-seven of these 51 cases (72.6%) passed through thehypoplastic preleukemic stage. The hematological findings tended to bemostly atypical at the time of leukemia diagnosis. In our clinic we haveexamined 22 cases of acute leukemia with hypoplastic marrow. They werecharacterized by poor clinical and physical signs (such as fever, petechiae andhepatosplenomegaly), slow progress, aleukemic with few or no leukemic cellsin the peripheral blood and hypoplastic marrows. Some of these patients wereobserved under the clinical diagnosis of hypoplastic anemia for a relativelylong time until leukemia was diagnosed. From these data, it may be suggestedthat a close relationship exists between the hypoplastic preleukemic stage andacute, mostly atypical, leukemia. Sex and age distributions of hypoplasticpreleukemic cases may give some clues, although the data are variable exceptfor the elderly who are more frequently affected. In the elderly, the bonemarrow tended toward hypofunction (19), and in elderly patients with leuke-mia, the clinical and hematological findings tended to be atypical (20). Thesepoints were helpful in the diagnosis of the hypoplastic preleukemic stage asthe initial step of leukemia in elderly patients.The present S4Tvey found that a hypoplastic preleukemic stage was fre-quent among patient$ that terminated in acute myelocytic leukemia. However,the following points are uncertain: (a) whether normal hematopoietic cells6Acta Medica Okayama, Vol. 29 [1975], Iss. 6, Art. 6http://escholarship.lib.okayama-u.ac.jp/amo/vol29/iss6/6Preleukemia 443become malignant in the course of so-called hypoplastic anemia or (b) whetherthe hypoplastic preleukemic stage is latent leukemia. The authors favor thesecond hypothesis. Aplastic or hypoplastic anemia was reported by Ehrlich(21) in 1888. Since then, this term has been loosely applied to cases withpancytopenia and hypoplastic marrows. Other hematological diseases may beexcluded if more rigid examinations were performed. Our investigation sug-gests that the hypoplastic preleukemic stage is characterized by the coexistenceof a relative erythroid hyperplasia and a slight increase of myeloblasts in thebone marrow, which is seldom found in so~cal1edhypoplastic anemia. Hypo-plastic preleukemia should be suspected in the presence of pancytopenia andhypocellular or hypoplastic marrow with a relative erythroid hyperplasia anda slight increase of myeloblasts.REFERENCES1. Hiraki, K. and Irino, S.: Mechanism of chemical leukemogenesis. Acta Hematol. Jpn.28, 860, 1965.2. Soda, H.: Studies on the leukemogenesis of mouse leukemia by X-irradiation. I.Changes in the preleukemic stage. Okayama Igakkai Zasshi 77, 1, 1965.3. Sezaki, T., Takahashi, 1., Nagao, T., Kitajima, K., Irino, S. and Hiraki, K.: Initialhematological pictures of Rauscher virus induced mouse leukemia. Acta Hematol. Jpn.34, 3, 1971.4. Block, M., Jacobson, L. D. and Bethard, W. F.: Preleukemic acute human leukemia. J.Amer. Med. Assoc. 152, 1018, 1953.5. Meacham, G. C. and Weisberger, A. S.: Early atypical manifestations of leukemia. Ann.Intern. Med. 41, 780, 1954.6. Williams, M. J.: Myeloblastic leukemia preceded of prolonged hematological disorder.Blood 10, 502, 1955.7. Rubinstein, M. A.: Early (preleukemic) diagnosis of leukemia. Proc. VIll. Congr. of Hemat.1, 1053; 1957.8. Roberts, B. E., Abbott, C. R., Fortt, R. W. and Pyrah, R. D.: Preleukemia; A report offour cases. Acta Hematol. (Basel) 39, 20, 1968.9. Blair, T. R., Bayrd, E. D. and Pease, G. L.: Atypical leukemia. J. Amer. Med. Assoc. 198,139, 1966.10. vilter, R. W., Jarrold, T., Will, J. j., Fredman, B. I. and Hawkins, V. R.: Refractoryanemia with hyperpiasic bone marrow. Blood 15, 1, 1960.II. Bjorkmann, S. E.: Chronic refractory anemia with sideroblastic bone marrow. Blood11, 250, 1956.12. Blackburn, E. K.: Pernicious anemia complicated by granulocytic leukemia. J. Clin.Pathol. (Lond) 10, 258, 1957.13. Jenkis, D. E. and Hartmann, R. C.: Paroxysmal nocturnal hemoglobinuria terminatedin acute myeloblastic leukemia. Blood 33, 274, 1969.14. Ben-Ishey, D., Freund, M. and Groen, J. J.: A case of autoimmune hemolytic anemiawith circulating cold agglutinins presenting for many years as "hypersplenism" andterminating in leukemia. Blood 22, 100, 1963.15. Sugano, H.: Leukemogenesis arising from blood disease among atomic bomb survivors.Acta Hematol. Jpn. 23,6, 1960.16. Uchino, H. and Kamata. H.: Studies on detection of preleukemic stage. J. Jpn. Med.7Takahashi et al.: Preleukemia: hematological disorders prior to onset of leukemiaProduced by The Berkeley Electronic Press, 1975444 1. TAKAHASHI, T. NAKANISHI, j.SAKATO, H. MIKOCHI, K. KITAJIMA and K. HIRAKIAssoc. 67, 11, 1415, 1972.17. Hirafuku, I. and Shimamine, T.: On the borderland of aplastic anemia and leukemia.Acta Hematol. Jpn. 27, 131, 1964.18. Takahashi, I., Kinoshita, H., Moriwaki, H., Shimada, A., Saito, K., Nagao, T., Ishizaki,M. and Kitajima, K.: Clinical studies on leukemia with hypoplastic preleukemic stage.Jpn. J. Glin. Hemat. 12,61, 1971-19. Hiraki, K.: Studies on the bone marrow in elderly persons. Jpn. J. Geriatr. 8, 47, 1971.20. Kitajima, K., Takahashi, 1., Ishizaki, M., Kinoshita, H., Moriwaki, M. and Kamimura,0.: Atypical leukemia. Jpn. J. Glin. Med. 30, 2, 105, 1972.21. Ehrlich, P.: Ueber einen Fall von Anaemie mit Bemerkungen ueber regenerative Ver-aenderungen des Knochenmarks. Gharite Ann. 13, 300, 1888.8Acta Medica Okayama, Vol. 29 [1975], Iss. 6, Art. 6http://escholarship.lib.okayama-u.ac.jp/amo/vol29/iss6/6

A case of autoimmune hemolytic anemia with circulating cold agglutinins presenting for many years as &quot;hypersplenism&quot; and terminating in leukemia.

Atypical leukemia.

Clinical studies on leukemia with hypoplastic preleukemic stage.

Early (preleukemic) diagnosis of leukemia.

Early atypical manifestations ofleukemia.

Initial hematological pictures of Rauscher virus induced mouse leukemia.

Leukemogenesis arising from blood disease among atomic bomb survivors.

Mechanism of chemical leukemogenesis.

Myeloblastic leukemia preceded of prolonged hematological disorder.

On the borderland of aplastic anemia and leukemia.

Paroxysmal nocturnal hemoglobinuria terminated in acute myeloblastic leukemia.

Pernicious anemia complicated by granulocytic leukemia.

Preleukemia; A report of four cases. Acta Hematol.

Preleukemic acute human leukemia.

Refractory anemia with hyperpiasic bone marrow.

Studies on detection of preleukemic

Studies on the bone marrow in elderly persons.

Studies on the leukemogenesis of mouse leukemia by X-irradiation. I. Changes in the preleukemic stage.

Ueber einen Fall von Anaemie mit Bemerkungen ueber regenerative Ver- aenderungen des Knochenmarks.

Preleukemia: hematological disorders prior to onset of leukemia

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