SUMMARY: Clinical and laboratory studies were made on thirty eight cases of acute promyelocytic leukemia (APL), characterized by proliferation of abnormal pomyelocytes and severe coagulation disturbances.
I. General Observations
1) Hemorrhagic manifestations and thrombocytopenia in APL were far more severe than in other types of acute leukemia.
2) Erythrocyte sedimentation rate was found to be within the normal range in about one-third of the cases, whereas was found to be accelerated in two-thirds. But its acceleration was less prominent than in other types of acute leukemia. No significant correlation was found between erythrocyte sedimentation rate and plasma fibrinogen level.
II. Cytological Studies
1) Compared with the promyelocytes in chronic myelogenous leukemia, normal promyelocytes and the pathologic cells in monocytic leukemia, the abnormal promyelocytes in the bone marrow smears were more frequently oval or irregular in contour and wavy at the ridge of protoplasma, and had tongue or bud-like processes. Their nuclei were often bi- or tri-lobulated. The granules varied not only in size but also in color, and the small pinkish granules were numerous. These characteristics were less prominent in the peripheral cells, indicating the importance of bone marrow aspiration in the diagnosis of APL.
2) In transmission electron microscopy, the processes were revealed to contain organelles such as granular endoplasmic reticulum and granules, different from usual processes of the leukocytes. These processes were usually thin at the base and swollen at the top, and similar free bodies were detected near the cells. Granule release was noted. These findings indicate a secretion of a part of cytoplasma (a specific type of holocrine secretion?).
Around the freed organelles fibrin strands and platelet aggregates were recognized, suggesting their thromboplastic activity. The peculiar inclusions in the granular endoplasmic reticulum, which were found by our group and Ogawa (1969) and were revealed to be slices of honey comb by Hattori using goniometer, were found in six of 15 cases.
III. Coagulation Studies
1) More severe and various disturbances of coagulation and fibrinolytic systems were found in APL than in other types of acute leukemia: the decrease of the clotting and fibrinolysis factors, especially of fobrinogen, factors Vand VIII and plasminogen; the shortening of partial thromboplastin time in siliconized tube; the positive ethanol and protamine tests; the increase of cryofibrinogen; the prolongation of serial thrombin time 30'; the shortening of euglobulin lysis time; the increase of fibrinogen degradation products; the increase of circulating anticoagulants.
2) These disturbances were considered to be caused by hypercoagulation and hyperfibrinolysis, and were considered to induced in combination with thrombocytopenia and platelet dysfunction severe hemorrhagic tendency in APL.
3) Some cosideration was made on possible mechanisms of the decrease of fibrinogen, which occurred most frequently among the decrease of clotting factors.
In conclusion:
APL is considered to be a distinct clinical entity as one of the specific types of acute myelogenous leukemia. Its diagnosis can be made from cytological and hemostatic findings.

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In order to clarify the pathogenesis of severe bleeding tendency in patients with acute promyelocytic leukemia (APL), the procoagulant activity, fibrinolytic activity and the effect on vessels of APL leukocytes were studied.
From the results it was concluded:
1) The severe hemorrhage in APL is mainly caused by DIC resulted from the extremely potent tissue factor activity of the APL leukocytes.
2) The fibrinolytic activity of APL leukocytes was equal to or slightly higher than that of leukocytes from normal individuals or patients with chronic myelocytic leukemia. This activity does not appear to play a significant role in the emergence of bleeding in APL.
3) Increase in the permeability of venules of rat mesentery as well as increased incidence in the degranulation of mast cells around velules were observed when rat mesentery was exposed to the action of APL cell lysate. These phenomena may take some part in the development of bleeding in APL.

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Daunorubicin (DNR) was given at doses of 1 mg/kg for 7 consecutive days in the treatment of acute promyelocytic leukemia (APL). Heparin was administered concomitantly in order to suppress disseminated intravascular coagulation which was thought to be aggravated by increased supply of procoagulant due to massive destruction of atypical promyelocytes during the DNR therapy. Complete remissions were achieved in 5 of 9 cases treated with this regimen. On the other hand, fatal intracranial hemorrhages occurred in 4 cases before completion of the induction therapy. Remissions have been maintained for 235 and 172 weeks, respectively, in two cases, while relapse occurred in 23, 29 and 33 weeks in the remaining three cases. Reinduction of remission was attempted by the DNR therapy, but only partial remissions could be attained in two of the three cases.
Controversy over heparin in the induction therapy of APL should be solved further to improve the remission rate, although its use appears to be logical to prevent early death due to hemorrhages. DNR is widely accepted as the drug of first choice in APL in recent years. However, superiority of DNR in combination with other antileukemic agents to DNR alone remained to be clarified not only in the initial induction but also on relapse. Effective maintenance chemotherapy in APL also requires to be established.

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Clinicopathological studies in 29 cases of acute promyelocytic leukemia (APL) which were examined both blood smear and coagulation-fibrinolytic studies, was performed. On the other hand, 14 cases of acute granulocytic leukemia, 8 cases of highly treated acute granulocytic leukemia and 5 cases of acute monocytic leukemia from the similarity of blood cells, were studied. The author concluded that APL was a specific variant of acute myelogenous leukemia, in which coagulation-fibrinolytic disturbance played an important role in clinical course. Morphological changes in bone marrow of APL which were treated by chemotherapy showed the same in acute myelogenous leukemia, such as fibrosis, fatty metamorphosis and reticulosis. Size and degree of thrombi in various organs of APL differed from the cases of gastric carcinoma. This fact suggest that some characteristics might be found in various disease with DIC.
As for the fibrin clearance from blood, endotoxin injection into rabbit was performed for 21 days with measurement of blood cell counts and coagulation-fibrinolytic activity. That fibrin in blood stream was taken most markedly in Kupffer's stellate cells of the liver among the reticuloendothelial system proved by microscopic, electron microscopic and immunofluorescence method. Moreover, the author examined the liver of APL with ordinary microscopic, electron microscopic and immunofluorescence method. Kupffer's stellate cells contained numerous fibrin and fibrin products, showing positive results with antihuman fibrinogen antibody, antihuman FDP-D and E antibody.

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Human peripheral lymphocytes can be separated into subpopulations, T, B and “null” cells, based upon receptors on their cell surface. We have analyzed malignant cells from 39 patients with various lymphoproliferative diseases, including nine patients with T-cell leukemia of adult onset type. Cells in adult T-cell leukemia were positive for cytotoxicity test with ATS and sheep red cell rosette and negative for cytotoxicity test with ABS, surface immunoglobulins and complement receptors. Mitogenic response to PHA and ATS were negative. Skin affection was present in six, and splenomegaly in five. Although Sézary cells with cerebriform nuclei appeared in none, cells with irregular or indented nuclei were frequent. Bone marrow was markedly affected by leukemic cells. Clinical course is generally chronic, but rapid terminal progression is a common feature. All but one were born in Kyushu. The geographical distribution of the cases indicates a possible high incidence of adult T-cell leukemia in the Kyushu district, especially Kagoshima Prefecture.

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1) Burkitt's lymphoma is likely to be B cell origin because of the presence of B cell markers. There are accumulating evidences which indicate Epstein-Barr (EB) viral etiology. Only B cell population was infected and transformed by EB virus when cord lymphocytes were cultured in the presence of the virus. Therefore B cell-tropism of the virus seemed to be the reason that Burkitt's lymphoma is B cell tumor.
Lymphocytosis in infectious mononucleosis (IM) caused by EB virus was proved due to the expansion of mainly T cell compartment. Most of the atypical lymphocytes were identified as T cells. Lymphoproliferative changes in IM seemed, therefore, to be the expression of T cell response to EB virus infection.
2) Leukemic cells from 42 cases with acute lymphoblastic leukemia were studied for T and B cells markers. Ten were identified as T cell type, while remaining were null cell type except one which had B cell markers. Infiltrative changes was more remarkable, relapse occurred earlier and survival time was shorter in leukemia of T cell type as compared with null cell type.
All of T type leukemic cells had poor stimulant effect in mixed lymphocyte culture reaction while 70% of null cell type simulated DNA synthesis of co-cultured lymphocytes well. T cell type seemed to have higher proliferative activity when their mitotic index and DNA synthesis were estimated.

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The membrane properties of lymphocytes in 19 patients with chronic lymphocytic leukemia (CLL) and allied disorders were studied by immunofluorescence, rosette formation with sheep erythrocytes and anti-T-cell antiserum.
The results were as follows:
1) Ninteen patients with CLL were classified into three categories according to B and T cell markers of lymphocytes: CLL of B-cell type: 12 cases, CLL of Non-B or T-cells: 4 cases, CLL of T-cells: 3 cases.
2) Most of B-cell type CLL were found to comprise a monoclonal population with one heavy chain and either kappa or lamda chain.
3) The predoninant surface immunoglobulin identified on lymphocytes was IgG of either kappa or lamda light chain type.
This finding formed a striking contrast to predominant surface immunoglobulin of IgM type of lymphocytes from CLL patients in published studies of Europe and America.
4) Several CLL patients were found to have a relatively high proportion of cells positive for Δ-chain, but Complement-receptor appeared to be missing or reduced from CLL lymphocytes.
5) In two patients with IgG-bearing lymphocytes, the serum contained a circulating IgG M-component.
6) Problem about oncogenicity of CLL lymphocytes was discussed.
7) In prolymphocytic leukemia, leukemic type of malignant lymphoma with T-cell nature and Sézary's syndrome, strong similarity were observed in hematological and clinical pictures as well as cell surface nature (T-cell property)

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In recent years, there have been rapid advances in the field of immunology and cytology, particularly with respect to the primary lymphoreticular disorders. The possible interrelationship in various so called reticulosis was attempted to make clear from the observation of surface markers on the abnormal lymphoid cells, using the immunologic technics and cytochemical methods for circulating blood.
Patients with the following kinds of reticulosis were studied; acute and chronic essential leukemic reticulosis (ELR), reactive leukemic reticulosis (RLR), macroglobulinemia (Waldenström) and mycosis fungoides. In addition, patients with reticulum cell sarcomatosis (RCS), lymphosarcomatosis (LS), monocytic leukemia and Hodgkin's disease were also studied and were compared with reticulosis.
The abnormal lymphoid cells in these disease were inspected with cytologic findings light, phase contrast and electron microscopically, cytochemical activities and surface markers.
The abnormal lymphoid cells in acute ELR were large and had spiny cytoplasmic contours on phase contrast microscopy. The tartrate-resistance was evident in the acute ELR cells with strong acid phosphatase activity. The cells were confirmed to be T-cell nature. The chronic ELR cells showed to have T-cell properties and the morpholgic similarities to the large lymphocyte. On the other hand, the abnormal cells in RLR were cytologically almost same in comparison for the acute ELR cells, however the surface markers were the B-cell type. The lymphoid cells from macroglobulinemia were confirmed to be B-cell type, while the atypical lymphocytes in mycosis fungoides were shown to be T-cell type. The surface markers of abnormal cells in other RES-related disorders, except for Hodgkin's disease, were seen also to be B-cell type.

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Two cases with hairy cell leukemia are presented, who show typical clinical course and findings.
Phase contrast microscopical observation is most excellent and of facility to identify the hairy cell among various morphological observation techniques. Tartrate-resistant acid phosphatase was revealed in hairy cells in both cases not only by histochemical method but also by biochemical one. The enzyme, especially tartrate-resistant, however, was found in other hematological malignancies, B- and T-CLL cells, RCS cells and monocytic leukemia cells. Surface markers were the same as those in the literatures. PHA response was low and delayed, but blastoid-transformation was obviously observed in a case.
Antisera was prepared against hairy cell according to the method producing anti-lymphocyte serum. The specificity of the serum against hairy cell was confirmed by cytotoxicity test following several absorption procedures. Anti-hairy cell serum also reacted to B-CLL cells and RCS cells. These cross-reactivities suggest that hairy cell is closely related to both B-CLL cell and RCS cell.

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