Conversion of acute leukemia from a T-lymphoid to a myeloid phenotype

A 7-year-old girl with an acute leukemia was reported whose blasts showed conversion from a T-lymphoid to a myeloid phenotype. At the onset of the disease, the blasts were negative for peroxidase and displayed FAB L1 morphology. Surface marker analysis revealed only CD7 antigen. Although complete remission was achieved, an extramedullary relapse was identified as having a several subcutaneous tumors 15 months later. Tumor cells showed the same marker expression as that of the blasts at the onset. After short term culture without an addition of any differentiation stimulators, the blast cells expressed CD2, CD3, CD4, CD8, and CD25 antigens. The karyotype was 46, XX, t(12; 21) (p11; q22). The intensive chemotherapy and radiation therapy were carried out, however, a hematological relapse occurred 12 months later. At this time, the blasts were strongly positive for peroxidase and expressed HLA-DR and CD33 antigens with disappearance of the CD7 antigen. Chromosome analysis revealed the additional abnormalities (del (7) (p15), -17, +der (17) t (17;?) (p13;?].     

Recurrent spontaneous regression of aleukemic leukemia cutis in a girl with acute monocytic leukemia

Aleukemic leukemia cutis is a rare form of leukemia manifestation, defined as a skin infiltration of leukemic cells with no evidence of leukemia in the bone marrow. A 4-month-old girl was referred to our hospital because of exanthema that appeared and regressed repeatedly. Histological examination revealed partial infiltration of histiocytic cells in the skin lesion. However, the diagnosis could not be made at that time. At 9 and at 13 months old, appearances of exanthema similar to the previous time were combined with systemic fever, abnormal coagulation tests, and the marked increases of atypical lymphocytes in peripheral blood: however, these symptoms resolved spontaneously. At 14 months old, deterioration of the exanthema and an increase in the peripheral leukocyte counts were observed. Bone marrow aspiration revealed the predominance of monocytic blasts (76.4%), and the patient was diagnosed as having acute monocytic leukemia (M5b) with leukemia cutis. Complete remission was obtained with standard chemotherapy. Six months after the therapy was completed, an extramedullary relapse occurred in the inguinal lymph nodes, which was successfully treated with allogeneic bone marrow transplantation from an HLA-matched unrelated donor, and the patient has been free of disease for two years after the transplantation.     

Acquisition of Philadelphia chromosome with bcr rearrangement concomitant with transformation of refractory anemia with excess of blasts with 8 trisomy into acute myelogenous leukemia

A case of Philadelphia (Ph1) chromosome positive acute myelogeneous leukemia (AML) following a refractory anemia with excess of blasts (RAEB) with 8 trisomy is reported. The 80-year-old man developed pancytopenia during the course of follow-up after the surgical operation of the carcinoma of the sigmoid colon and the rectum for which no irradiation therapy nor chemotherapy had been applied. The diagnosis of RAEB was made according to the diagnostic criteria proposed by FAB co-operative group. Chromosomal analysis revealed 8 trisomy in 54% of the metaphases of bone marrow cells. The remainders showed normal karyotype without Ph1 chromosome. He was on androgenic steroid and activated Vitamin D3 without significant changes in the clinical and the hematological features until 3 months later when many atypical blasts appeared in the peripheral blood. The diagnosis of AML (M2) was made. Chromosomal analysis revealed Ph1 chromosome with the typical 9;22 translocation in 100% of the examined cells. 8 trisomy was not detected any more. Southern blot analysis using bcr probe showed bcr rearrangement. He was treated with a small doses of Ara-C. There was some reduction in the number of blasts in the peripheral blood. However, he died of septicemia 2 months later. The present case indicates that Ph1 positive acute leukemia with bcr rearrangement is not necessarily considered as a blastic transformation of chronic myelogeneous leukemia and such a cytogenic abnormality can appear in a leukemic transformation of myelodysplastic syndrome.     

A case of monoblastic crisis of CML beginning with extramedullary tumor formation in a rib]

A patient with CML showed monoblastic crisis which started with extramedullary tumor formation in a rib before medullary involvement. She was diagnosed as having CML in 1984 at the age of 57. In February 1990, she was admitted to Furukawa City Hospital because of extramedullary blastic crisis beginning at the right 5th rib. At that time, the bone marrow revealed 4.6% blasts. On March 5, after one course of chemotherapy, she was transferred to our hospital for radiotherapy. Hematological findings were WBC 10,100/microliter with 10% blasts, Hb 10.9 g/dl, platelet 3.7 x 10(4)/microliters. Bone marrow aspiration was unsuccessful. The blasts in the peripheral blood were negative for peroxidase and chloroacetate esterase; but positive for naphtylbutyrate esterase. The leukemic cells were positive for CD13, CD33, and had phagocytic activity. Chromosomal analysis revealed 46XX with Ph1 chromosome and some additional anomalies. Southern blot analysis of tumor cells shows BCR rearrangement. These findings suggest that the blasts were immature monocytic cells, and we conclude that this is a rare case of extramedullary monoblastic crisis of CML.     

Neural cell-adhesion molecule (CD 56)-positive,t(8; 21) acute myeloid leukemia (AML,M-2) and granulocytic sarcoma

A 49-year-old man with t(8; 21) acute myeloid leukemia relapsed 8 months after successful induction chemotherapy with a paraspinal granulocytic sarcoma. There was no evidence of leukemia in the bone marrow at relapse. At initial presentation, the blasts coexpressed CD 15, CD 33, CD 34, CD 45, CD 19, and CD 56 (a neural cell-adhesion molecule). Expression of certain cell-adhesion molecules on leukemic blasts may determine a tendency to develop extramedullary relapse. The co-expression of CD 56 may have a role in the predisposition of t(8; 21) AML to develop GS.     

Transformation of myelodysplastic syndrome to acute lymphoblastic leukemia: A case report and review of the literature

Myelodysplastic syndrome (MDS) often transforms into acute leukemia, usually of a myeloid phenotype. However, the transformation of MDS into acute lymphoblastic leukemia (ALL) is extremely rare. We present a case of refractory anemia with excess of blasts (RAEB) that transformed into ALL. MDS (RAEB) was diagnosed in a 68-year-old Japanese woman in August 2001. Two months later, MDS progressed to erythroleukemia (French-American-British [FAB]classification, acute myeloid leukemia [AML]-M6), and in December, 2001, she was treated with combined chemotherapy containing aclarubicin, cytarabine, and granulocyte colony-stimulating factor, which improved her clinical symptoms. However, 1 month after the chemotherapy, she developed ALL. The blasts at that time had a markedly basophilic cytoplasm with multiple cytoplasmic vacuoles, and their morphology mimicked that of ALL-L3. The blasts also expressed CD13, a myeloid marker, in addition to lymphoid markers. Southern-blot analysis revealed rearrangement of the immunoglobulin heavy chain, but no additional chromosomal abnormality characteristic of ALL-L3 was detected. The patient was treated with chemotherapy, but she developed tumor lysis syndrome and died of multiple organ failure. Although the precise mechanism of lymphoid transformation is not yet fully understood, this case clinically supports the nature of MDS as a pluripotent hematopoietic stem cell disorder.     

Myeloid Sarcoma Occurring in the Maxillary Gingiva: A Case without Leukemic Manifestations

Myeloid sarcoma (MS) is a localized extramedullary mass of immature granulocytic cells that usually occurs in patients with acute myeloid leukemia (AML) or myeloproliferative disorders. It may rarely precede peripheral blood or bone marrow involvement, presenting a diagnostic challenge. Although MS may be found in any location, an intraoral occurrence is rare. In this report we describe a rare case of a patient with nonleukemic MS of the maxillary gingiva. The histologic specimen was first interpreted as non-Hodgkin's lymphoma. The correct diagnosis was reached after extensive immunohistologic studies. The malignant cells were myeloperoxidase positive, lysozyme positive, CD45+, CD68+, CD3-, CD10-, CD19-, CD20-, CD30-, CD34-, CD56-, CD79a-, S100-, and chloroacetate esterase negative. Induction therapy with FLAND (fludarabine, Ara-C, mitoxantrone, and dexamethasone) was started, but the patient did not achieve a remission. Some weeks later, the patient presented pleural effusion and paralysis of the seventh cranial nerve on the left side. She died a few days later. The present case indicates the importance of a correct initial diagnosis for adequate therapy, which is often delayed because of a high misdiagnosis rate. If the MS is treated without intensive chemotherapy for AML as soon as possible, the prognosis will be poor.     

Podocalyxin is expressed in normal and leukemic monocytes

We have investigated the expression of podocalyxin in primary cultures of leukemic blast cells from 73 patients with acute myeloid leukemia. Podocalyxin was expressed at moderate levels in 15 patients and at high levels in 13 patients. The analysis of membrane markers showed that Podocalyxin expression in leukemic blasts was associated with a monocytic immunophenotype. Cases of podocalyxin-positive acute myelogenous leukemia had high blast cell counts at diagnosis and elevated CD123, CD135, VLA-4 and CXCR4 expression, features associated with poor prognosis. Podocalyxin expression in leukemic blasts was coupled with the concomitant expression of VEGF-R1, -R2, -R3 and Tie-2, the capacity to release VEGF-A and angiopoietin1 and the ability to differentiate into endothelial cells under appropriate culture conditions. These findings show that podocalyxin is a marker of acute myeloid leukemia with a monocytic phenotype and suggest that podocalyxin-positive cases of acute myeloid leukemia originate from the malignant transformation of progenitors common to the myeloid and endothelial lineages. These observations suggest a possible relationship between the monocytic lineage and podocytes.     

Mucosa-associated lymphoid tissue type lymphoma of the gallbladder associated with acute myeloid leukemia.

We describe a patient with mucosa-associated lymphoid tissue (MALT) type lymphoma of the gallbladder who developed concurrent acute myeloid leukemia (M2). She was admitted because of progressive jaundice and underwent cholecystectomy. Histologic examination of the gallbladder showed diffuse proliferation of atypical lymphoid cells and a formed lymphoepithelial lesion. Because of progressive thrombocytopenia, a bone marrow tap was performed 25 days after the operation. Bone marrow contained 65.5% blasts, and was positive for peroxidase, CD33 and HLA-DR, and negative for lymphoid markers. We discuss the rare association of these disorders.     

CD 56-positive acute myeloid leukemia (AML-M 1) with t(16;21) (p11;q22) presenting an extramedullary tumor in the right breast at relapse

A 46-year-old woman was diagnosed as having acute myeloid leukemia (M 1) with translocation t(16;21) (p11;q22). The leukemic cells were positive for CD 13, CD 33, CD 34, CD 41, CD 56 and HLA-DR. After induction chemotherapy, the patient achieved complete remission (CR). However, 8 months later she relapsed with various additional chromosomal abnormalities. Although the patient achieved a 2nd CR after re-induction chemotherapy, the patient had extramedullary tumors in the right breast twice and relapse occurred frequently. The tumor cells were characterized by the same immunophenotypes and t(16;21) with additional 1 q trisomy. Although there was no evidence of hematological relapse, another type of 1 q trisomy was observed. Furthermore, an increase of abnormalities with 1 q trisomy was noted concomitant with re-increase in the number of blasts. The patient underwent allogeneic bone marrow transplantation (BMT), but she died from BMT complications. The case could have been a karyotype of t(16;21) with additional chromosomal abnormalities through consecutive approaches. Because of the high occurrence rate of relapse, we consider various additional chromosomal abnormalities and the expression of CD 56 as prognostic factors of this condition.     

Granulocytic sarcoma developing in lymph nodes

A 77-year-old man was admitted to a hospital because of a left cervical tumor. He was initially diagnosed as having non-Hodgkin lymphoma, diffuse large cell type, Ann Arbor stage IV, and transferred to our hospital for chemotherapy. Flow cytometric analysis of the left axillary lymph node cells derived from a biopsy specimen showed that in addition to lymphoid surface markers (CD5, 7, 21), myeloid surface markers (CD11b, 33, 34) were also positive. The diagnosis of malignant lymphoma was therefore confirmed. The patient, was treated with THP-COP therapy, which proved very effective. Thereafter, a biopsy specimen was found to be positive for MT1 (CD43) staining but negative for myeloperoxidase and chloroacetate esterase staining on immunohistochemistry. Furthermore, no rearrangement of the IgH JH, TCR C beta 1 or TCR J gamma gene was detected by Southern blot analysis. On basis of these findings and the previous results of flow cytometry, we changed the diagnosis from malignant lymphoma to granulocytic sarcoma. THP-COP therapy was continued, and complete remission was achieved. Two months later, however, the patient developed acute myelocytic leukemia (AML M1) and received DCP therapy, but he died of pneumonia.     

Lineage switch on recurrence from minimally differentiated acute leukemia (M0) to acute megakaryocytic leukemia (M7)

Phenotypic switch in acute leukemia is a rare phenomenon. We report on a female infant with minimally differentiated acute leukemia (M 0) which underwent a lineage switch on relapse. In March 1997, a 1-year-8-month old girl was admitted to our hospital with a high-grade fever and generalized purpura. Bone marrow showed 84% blasts. The blasts were negative for peroxidase, periodic acid-Schiff and alpha-naphthyl butyrate esterase. Immunophenotypic analyses of the blast cells were positive for CD 13, CD 33 antigens, as well as CD 34. Lymphoid markers all were negative. Though some blasts morphologically demonstrated cytoplasmic blebs, CD 41 was negative and ultrastructural platelet peroxidase was absent. Based on these hematological features, the patient was diagnosed as having AML-M 0. She was treated according to the Children's Cancer and Leukemia Study Group schedule and a complete remission was achieved 1.5 months after starting induction therapy. However, she relapsed in spite of continued chemotherapy in July 1997, when the cytomorphological pattern changed and the patient was diagnosed both morphologically and immunologically as having M 7. Electron microscopy revealed platelet peroxidase (+) and CD 41 (+). Cytogenetic studies on relapse demonstrated inv(3) (q 21 p 25). We attempted aggressive reinduction therapy, but without effect. The patient simultaneously developed severe pneumonia and died in February, 1998. A lineage switch on relapse and resistance to chemotherapy may be associated with the occurrence of genetic aberration.     

Activity of all-trans-retinoic acid in a case of central nervous system extramedullary relapse of acute promyelocytic leukemia

We describe a patient with an acute promyelocytic leukemia (APL) previously treated with two courses of cytarabin, idarubicin and all-trans retinoic acid (ATRA), who presented a medullary and meningeal relapse after 8 months of complete remission. A diagnosis of central nervous system (CNS) involvement was based on the appearance of APL blasts in the cerebrospinal fluid (CSF); magnetic resonance (MR) imaging was negative. The neurological symptoms were not evident at the time of recognition of the medullary recurrence, but appeared a few days later, when the patient had already received a reinduction treatment. When the CSF was first examined, showing atypical promyelocytes, there was no excess of blasts on bone-marrow examination. The patient was treated with ATRA and intrathecal administrations of cytoxic drugs, achieving a complete long-lasting CNS remission. The appearance of mature myeloid cells in the CSF during this treatment suggested a possible differentiating effect of ATRA towards extramedullary relapse.     

Prolonged lymphocytosis as the first manifestation of Hodgkin-like adult T-cell leukemia/lymphoma

Hodgkin-like ATLL is a rare variant of adult T-cell leukemia/lymphoma (ATLL), a disease caused by human T-cell lymphotropic virus type-1 (HTLV-1). At admission, a 46-year-old female presented with lymphadenomegaly, lymphocytosis, slight elevation of LDH blood level, and acid-alcohol resistant bacilli in sputum and was being treated for pulmonary tuberculosis (Tb). She had lymphocytosis in the previous 20 months. Serology for HTLV-1 was positive. Lymph node was infiltrated by medium-sized lymphocytes with scattered Hodgkin and Reed-Sternberg-like cells CD30+, CS1-4+, and CD79a+. Background cells were CD4+ and CD25+. A clinical diagnosis of favorable chronic ATLL was given. She was treated with chemotherapy but later progressed to acute ATLL and ultimately died. Hodgkin-like ATLL should be considered in the histological differential diagnosis with Hodgkin lymphoma since treatment and prognosis of these diseases are distinct. It is also important to search for HTLV-1 infection in patients with unexplained prolonged lymphocytosis.     

Treatment of a Child With Myeloid/NK Cell Precursor Acute Leukemia With L-Asparaginase and Unrelated Cord Blood Transplantation

A 2-year-old Japanese boy who presented with multiple cervical, axillary, and inguinal lymphadenopathy was diagnosed by immunocytochemical analysis as having myeloid/natural killer (NK) cell precursor acute leukemia. Leukemic blasts in the bone marrow were positive for CD56 (NK marker), CD7 (T-cell marker), CD33 (myeloid marker), CD34, and HLA-DR. Tumor cells in a lymph node were also positive for CD2, cytoplasmic CD3 (T-cell marker), CD7, CD33, CD34, and CD56, but negative for peroxidase staining and other T-cell, NK, and myeloid markers. Southern blot analysis showed no rearrangement bands for T-cell receptor delta and immunoglobulin heavy chain. Chromosomal analysis revealed 46,XY,inv(7)(p21q21). Neither chemotherapy for acute lymphoblastic leukemia nor that for acute myeloid leukemia induced remission in this patient. However, complete remission was achieved by the administration of L-asparaginase (6,000 U/m2 for 5 days). Because the disease was considered refractory to standard chemotherapy, cord blood transplantation was performed from an HLA 1-locus mis-matched unrelated donor. The conditioning regimen consisted of total body irradiation, cytarabine, and cyclophosphamide, and cyclosporine and short-term methotrexate were employed for graft-versus-host disease (GVHD) prophylaxis. Hematological reconstitution was rapid, and only grade I acute GVHD was observed. The patient has been in remission for more than 24 months after transplantation. Our findings indicate that combination therapy with L-asparaginase and allogeneic stem cell transplantation may be useful for the treatment of myeloid/NK cell precursor acute leukemia.     

Acute promyelocytic leukemia accompanied by scrotal Fournier's gangrene during ATRA treatment and relapsed as external ear tumor

A 43-year-old man was admitted because of gingival bleeding. A diagnosis of acute promyelocytic leukemia (APL) was made. He was given combination chemotherapy including all-trans retinoic acid (ATRA). During the myelosuppression stage, the patient developed Fournier's gangrene of the scrotum. He achieved complete remission and underwent a hemicastration procedure. Seven months later, bilateral external ear tumors developed. Biopsy specimens of the tumors revealed infiltration of APL cells. A second remission was obtained by chemotherapy including ATRA. However, bilateral ear tumors developed again 5 months later despite indications of normal marrow without proliferation of leukemic blasts. Irradiation successfully reduced the ear tumors, but the patient died of cerebral hemorrhage from a left frontal extramedullary tumor. This was a rare case of APL accompanied by Fournier's gangrene of the scrotum during ATRA treatment, and by extramedullary tumors of the external ear and brain during leukemic relapse.     

Expression of CD56/NCAM on hematopoietic malignant cells. A useful marker for acute monocytic and megakaryocytic leukemias.

We investigated the expression of CD56 (a neural cell adhesion molecule, NCAM) and CD57 in various hematopoietic and non-hematopoietic malignant cells, using Leu-19 and Leu-7 monoclonal antibodies. Although both molecules are commonly defined as a natural killer cell marker, we found that CD56 was highly expressed on blasts from patients with acute monocytic (4/6) and megakaryocytic (3/3) leukemias. In the latter, FACS two-color analysis revealed that leukemic megakaryoblasts simultaneously expressed CD56 and platelet-related antigens. Among leukemic cell lines, one myelocytic, three monocytic, and two megakaryocytic lines were positive for CD56. On the other hand, except for one large granular lymphocytic leukemia and one multiple myeloma cell line, none of the lymphoid leukemia cell lines or lymphoblasts from patients with acute lymphocytic leukemia (ALL) (0/15), non-Hodgkin's lymphoma (NHL) (0/2), and central nervous system (CNS) leukemia (0/2) reacted with Leu-19 antibody for CD56. The expression of CD56 in leukemia cells was not significantly affected by 12-O-tetradecanoylphorbol-13-acetate (TPA). By contrast, all hematopoietic materials were negative for CD57, while non-hematopoietic neuroblastoma cell lines expressed this molecule (4/5) as well as CD56 (5/5). Cytogenetically, the NCAM gene is located at chromosome 11q23, and chromosome breaks were often observed at this location in various leukemias. Blasts from all five acute non-lymphocytic leukemia (ANLL) patients and cell lines with 11q23-proximal chromosomal breaks were positive, while those from one ALL patient with an 11q23 abnormality were negative for CD56, necessitating further studies to clarify the link between the 11q23 abnormality and CD56 expression.     

An autopsy case of acute mixed lineage leukemia with monosomy 7 in a child

A five-year-old boy initially diagnosed common ALL was developed to acute myelomonocytic leukemia. At onset, the bone marrow was hypercellular and 77% of the cells were blasts, mainly lymphoblast-like cells and cytogenetic study demonstrated 45, XY, -7 in all blasts. Cytochemically most of those blasts were negative for peroxidase, sudan black B, alpha-NB esterase staining. The immunological phenotype was J5 (CD10)+, I2 (HLA-DR)+, SmIg-, CyIgmu-, Leu1 (CD5)-, OKT11 (CD2)-, MY7 (CD13)-, suggesting common ALL. Eight months later, the bone marrow cells were occupied with large sized blasts which were almost positive for peroxidase stain and the cells showed coexpression of Mo1 (CD11b)+, MY4 (CD14)+, MY7+, MY9 (CD33)+, MCS2 (CD13)+, I2+, J5-, B4 (CD19)-, Mo2 (CDw14)-, at relapse. He died 2 years and 6 months after his initial diagnosis. An autopsy was performed which revealed generalized infiltration of leukemic cells and aspergillosis of the lung. In general, monosomy 7 is associated with myelodysplastic syndrome in childhood, and is terminated to acute myeloblastic leukemia. In this case, bone marrow blasts demonstrated monosomy 7 cytogenetically, and this case was considered as an acute mixed lineage leukemia of bilineal type. And this case proved that a monosomy 7 can also be terminated to acute mixed lineage leukemia with both lymphoid and myeloid phenotypes.     

Spontaneous differentiation from myeloperoxidase-negative acute nonlymphocytic leukemia to acute myelomonocytic leukemia

We reported a 68-year-old woman with acute nonlymphocytic leukemia, in whom the leukemia transformed from poorly differentiated myeloperoxidase (MPO)-negative type into myelomonocytic type during the observation without chemotherapy. Hematological findings on admission revealed a leukocyte count of 3,500/microliters with 48% blasts and a platelet count of 9.2 x 10(4)/microliters. Bone marrow aspiration showed 68.2% infiltration of blasts negative for MPO. Sudan black B and esterase stains. By electron microscopy MPO was detected in the endoplasmic reticulum and nucleoenvelope of the blasts. Large vacuole-like granules were MPO-negative. She was observed without administration of any antileukemic agent or an immunopotentiator. The leukocyte count rose gradually, in association with increases in the relative and absolute counts of mature neutrophils and monocytic cells, and the platelet count. Twenty-six months after the initial diagnosis, a blood examination showed a leukocyte count of 74,300/microliters with 20.5% mature neutrophils and 15.5% monocytic and a platelet count of 31.4 x 10(4)/microliters. Cytological, cytochemical, ultrastructural and immunological studies of the bone marrow cells showed features compatible with acute myelomonocytic leukemia (FAB M4). This case is unusual in respect that poorly differentiated ANLL transformed spontaneously into moderately differentiated ANLL.