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.     

Philadelphia chromosome (Ph1) positive acute myelomonocytic leukemia with esophageal cancer: a case report]

A 62-year old male was admitted to our hospital because of fever and dysphagia on November 14, 1987. The peripheral leukocyte count was 174,400/microliters with 93% blasts and bone marrow aspiration showed that 90.4% of nucleated cells were blasts positive for both myeloperoxidase and alpha-naphthylbutyrate esterase. Chromosome analysis revealed a karyotype of 45XY, 9q+, 16q+, -20 and 22q-. Esophageal X-ray and endoscopy showed abnormalities. Esophageal biopsy revealed squamous cell carcinoma. He was diagnosed as having Ph1 positive acute myelomonocytic leukemia (AMMoL, M4) and esophageal cancer. He was treated with BHAC-DMP and intermediate-dose ara-C therapy for leukemia and a complete remission was obtained by March 25, 1988. As treatment for esophageal cancer, radiation therapy (total 4,200 cGy) was given and followed by chemotherapy with CDDP and 5-FU. However he died on April 8, 1988. Autopsy findings showed disseminated invasion of esophageal cancer. Ph1 positive AMMoL associated with esophageal cancer is extremely rare.     

Mixed blast crisis with the cytogenetic evidence of three clonal evolutions

A 46-year-old man was diagnosed as having chronic myelogenous leukemia (CML) in chronic phase in Dec. 1985. In Dec. 1987, anemia and leukocytopenia progressed, and the percentage of blast cells increased in the bone marrow. The blast cells were lymphoblastoid and positive for TdT. It was treated as a lymphoid crisis with vincristine and prednisolone, and complete remission was achieved. However, the blasts (11%) were observed in the bone marrow in Mar. 1988, and the chromosomal analysis revealed 46, XY, t (2q-; 11q+), t (9q+; 22q-) in 13 out of 20 cells. In June, the percentage of the blasts increased again, but chromosomal analysis showed a different karyotype, 46, XY, t(2p-; 11p+), t(9q+; 22q-) which was observed in 9 out of 10 cells. Then, myeloblastoid cells increased rapidly in spite of the chemotherapy in Dec. 1988. The chromosomal analysis showed 46, XY, 2p-, 7q-, 9q+, 11p+, 22q- in all analyzed cells. The rearrangement of the bcr gene could be detected by the Southern blotting. The blasts were positive for CD7, CD11, CD13, CD33, CD36, CD41 and CD42, suggesting that the blasts had the surface phenotypes of both myeloid and megakaryocytoid-lineage. This is a case with the mixed blast crisis that changed from the lymphoid to the myelo-megakaryocytoid in nature, in which three clonal evolutions were observed during the clinical course.     

Biphenotypic acute leukemia with Ph1 chromosome, M-BCR-, myeloperoxidase+, and CALLA+]

A 63 year-old woman was referred to our hospital because of fever and increased number of blasts in the bone marrow. On physical examination she had slight hepatomegaly but no splenomegaly. Laboratory tests disclosed a hemoglobin level of 8.5 g/dl; a WBC count of 13,200/microliter with 26% blasts; a platelet count of 51,000/microliter. A bone marrow aspirate was normocellular with 74% blasts and 37% blasts were stained positive for myeloperoxidase. Cell surface markers for HLA-DR, CD10, CD19, CD13, CD33 were positive. Karyotype analysis revealed 46, XX, t (9q+; 22q-) and 45XX, -7, t (9q+; 22q-). Southern analysis showed rearrangement of immunoglobulin heavy chain but not T cell receptor beta gene. Rearrangements in M-BCR were not detected with 5' or 3' bcr probes. After 2 courses of chemotherapy, blasts decreased to 7% with recovery of normal elements and 11 out of 20 metaphases of the bone marrow cells were normal karyotype. These findings suggest that this case was de novo Ph1 positive acute leukemia which demonstrated both lymphoid and myeloid features.     

Acute myeloblastic leukemia and hepatocellular carcinoma following Waldenstr?m's macroglobulinemia

A 54-year-old man was admitted to our hospital for precise examination of pancytopenia in October 1988. He had been cut off his left femur and irradiated because of osteosarcoma in 1954. After 30 years, he was diagnosed as Waldenstr?m's macroglobulinemia. Melphalan had been given 2 mg daily for 19 months until August 1988, when it was discontinued due to pancytopenia. Peripheral blood showed Hb 6.6 g/dl, platelet 40 x 10(3)/microliters, and WBC 2000/microliters with 33% blasts. Bone marrow showed normocellularity with 36% blasts. Although blasts were negative for peroxidase staining, surface marker analysis revealed myeloid (CD 13, CD 33) phenotypes. Chromosome analysis showed 45, XY, -7, inv (3). A CT scan of the liver showed a mass, 10 by 10 cm, compatible with hepatocellular carcinoma. He was treated with very low dose Ara-C without noticeable effect. Hepatic tumor gradually enlarged, and he died of hepatic failure. This is a rare case of quadruplicate malignancies. The chromosomal abnormality suggests that AML was secondary leukemia which might be associated with immunosuppression due to macroglobulinemia and/or melphalan therapy.     

Appearance of Philadelphia chromosome at relapse of erythroleukemia in a 12-year-old boy

A 12-year-old boy was referred to our hospital because of anemia and jaundice. On admission bone marrow smears were compatible with M6 classification of the FAB, revealing 74.5% erythroblasts of all nucleated cells and 40% blasts of nonerythroid cells. Karyotype analysis revealed 46, XY. Gene rearrangement within the breakpoint cluster region (bcr) on chromosome 22 was negative at this time. Complete remission was attained by a combination chemotherapy. However, at 10 months of remission, cytogenetic studies of the bone marrow demonstrated Ph1 positive (10%). One month later, the patient fully relapsed with a 75% Ph1 positive karyotype associated with positive bcr. Subsequently, the patient died of refractory leukemia.     

Essential thrombocythemia transformed to acute myeloblastic leukemia

A 48-year-old woman was referred to Tohoku University Hospital in November 1981 because of leukocytosis pointed out in a group examination. At that time white blood cell count was 26.8 x 10(3)/microliters with no blasts, platelet count 268.0 x 10(4)/microliters and hemoglobin 11.4 g/dl. Bone marrow aspirates showed marked increase of megakaryocytes (15,900/microliters). Bone marrow chromosome analysis revealed 46, XX, -18, +mar without Ph1 chromosome, and DNA analysis showed no bcr rearrangement. She was diagnosed as having essential thrombocythemia and was treated with busulfan. On November 1986, she developed remarkable leukocytosis with leukemic blasts. White blood cells reached 153 x 10(3)/microliters with 33% blasts. Her blasts were positive for peroxidase staining, but negative for platelet peroxidase on electron microscopic study and platelet specific glycoproteins. A diagnosis of acute myeloblastic leukemia (M2) was made. The patient received various combination chemotherapy, which was ineffective, and she died due to pneumonia on June, 1989. In Japan, there has been reported only 8 cases of essential thrombocythemia transformed to acute leukemia. The clinical pictures of these 9 cases were discussed.     

Myelodysplastic syndrome associated with marked eosinophilia and basophilia]

Myelodysplastic syndrome (refractory anemia with excess of blasts; RAEB) with marked basophilia and eosinophilia is described. An 82-year-old male was admitted to our hospital because of severe normocytic normochromic anemia (Hb 5.6 g/dl). The white cell count was 9,200/microliters with marked basophilia (34.5%) and eosinophilia (19.5%). The bone marrow aspiration also revealed both basophilia and eosinophilia, with blast contents of 9%. Diagnosis of RAEB was established. Although the treatment with red cell transfusion and ubenimex (Bastatin) was started, anemia was not improved. A karyotype of the bone marrow cells from this patient showed 47, XY, +8, i (17q), which has been observed as additional chromosomal abnormalities in blastic crisis of chronic myelogenous leukemia. The diagnosis of CML was not compatible with this case, because Ph1 chromosome and bcr gene rearrangement were negative. It is concluded that eosinophilia and basophilia might be derived from clonal abnormalities associated with MDS.     

Late appearance of Philadelphia chromosome with bcr gene rearrangement in an acute myelocytic leukemia patient

A case of acute myelocytic leukemia (AML-M2) with a late appearance of Philadelphia chromosome (Ph1) is presented. Chromosome analysis revealed a normal karyotype at the time of diagnosis and for 23 months, when hematological relapse occurred, accompanied by abnormal clones, 46, XX, t(9;22) (q34;q11) (78%) and 45,XX, -16, t(9;22) (q34;q11), del (5) (q13q31) (22%). The patient died of GVHD after bone marrow transplantation. Molecular analysis confirmed bcr gene rearrangement in the cells with Ph1 chromosome. Acquisition of Ph1 chromosome during the course of hematological malignancies other than CML is extremely rare. This case is undoubtedly important for the understanding of leukemogenesis and the evolution of leukemia clones. The authors discussed possible mechanisms of Ph1 acquisition in the late stages of AML.     

Acute lymphocytic leukemia with Philadelphia chromosome and rearrangements of bcr gene and deletion of 5' side and of TCR-delta gene

A 58-year old man was admitted because of general malaise in April 1987. Physical examination revealed systemic lymphadenopathy and hepatosplenomegaly. The white blood cell count was 252, 900/microliters with 82% of blasts. Bone marrow aspiration contained 93.8% lymphoblasts, which were positive for TdT and negative for peroxidase reaction. Immunologic marker studies showed OKT 11 positive and CALLA negative. Cytogenetic analysis revealed a clone with 46, XY, t (9; 22) (q34; q11), del(5) (q15) in 12 of the 13 metaphases. Ph1 positive T-acute lymphoblastic leukemia was considered. After AdVP and following AdVEMP (induction) chemotherapy, complete remission was obtained in August 1987. Cytogenetic study at the remission stage showed complete disappearance of Ph1 positive clone. Treatment with BH-AC DMP protocol at the time of recurrence in November 1987, brought no improvement and he died of respiratory failure. Chromosome study at recurrence showed an additional complex abnormal karyotype (double Ph1, +2, 5q-, -10, -13, -17). DNA analysis revealed rearrangements of bcr gene with deletion of 5' side and of TCR delta gene, without any rearrangements in other immunoglobulin genes. From cytogenetic, immunophenotypic and genetic analysis the patient was diagnosed as having acute lymphocytic leukemia (FAB L1) with Philadelphia chromosome and rearrangements of bcr gene with deletion of 5' side and of TCR delta gene.     

Chromosome 21 rearrangement in a case of therapy-related myelodysplastic syndrome in multiple myeloma

A case of therapy-related myelodysplastic syndromes (t-MDS) in 66-year-old male patient is reported. The patient was diagnosed as having multiple myeloma in July 1983. Cyclophosphamide was given since September 1984, and melphalan was added since June 1986. Radiation therapy was not performed. Mild, slowly aggravating pancytopenia developed in July 1987. By December 1987, the hemoglobin level dropped to 6.0 g/dl, leukocytes to 2,800/microliters, and platelets to 15,000/microliters. At that time, 27% of the bone marrow cells were blasts and 23.3% monocytoid cells. Based on these findings, a diagnosis of t-MDS was made. He was managed by supportive care only, but the monocytoid cells increased rapidly in number and he died of pulmonary bleeding in March 1988. Chromosomal banding studies of the bone marrow cells revealed dir ins [inv (17) (p13q21); 21] (q21; p13q22) in all the 11 metaphases examined, but chromosomes No. 5 and 7 were normal. However, Keldsen et al reported that chromosome 21q rearrangements were nonrandomly associated with t-MDS and t-acute nonlymphocytic leukemia.     

Myelodysplastic syndrome with complex chromosome abnormalities and peculiar fibril formation in granulocytes

We report a case of myelodysplastic syndrome with peculiar fibril formation in granulocytes shown through electron microscope and complex karyotypic abnormalities including ring chromosomes. The patient, a 76-year-old male, was consulted for mild pancytopenia in February 1987. After 5 month, his hematological findings showed severe pancytopenia getting worse rapidly and presence of blasts in the peripheral blood. He had slightly hypercellular marrow with marked trilineage dysplasia and increased number of blasts (12.6%). Chromosome analysis from the bone marrow cells revealed its various structural abnormalities, especially in No. 3, 4, 5, 7, 11 with translocation on 11q11, and large ring chromosomes derived from unknown one. By electron microscopic study, we observed bizarre structures, which was peculiar fibril formation as bundles of filament resembling actin paracrystals, throughout cytoplasm as well as within nucleus in granulocytes.     

Acute unclassified leukemia with bone marrow necrosis

Massive bone marrow necrosis was seen in a 42-year-old male with acute leukemia. In December, 1988, on admission, laboratory data revealed pancytopenia and a high level of serum LDH and ALKP. Bone marrow aspiration resulted in dry-tap and showed bone marrow necrosis in the bone marrow biopsy specimen. A bone marrow scintigraphy with 111In faintly visualized the bone marrow but visualized area was expanded in the extremities compared with normal subjects. The second bone marrow biopsy showed proliferation of blasts. In the middle of March, blasts began to appear in peripheral blood. The blasts were cytochemically negative for POX, Es, PAS, AcP, TdT and had surface markers CD3-, CD19-, CD33-, CD13-, LCA-, HLA-DR-. Even by investigation on rearrangement of the immunoglobulin heavy chain region, an origin of the blasts could not be determined. In April, the number of blasts in peripheral blood increased and hepatosplenomegaly developed rapidly. Therefore, he was put on the chemotherapy with vincristine and prednisolone, but he died of cerebral hemorrhage. The autopsy revealed widespread bone marrow necrosis. It has rarely been reported that massive bone marrow necrosis is found prior to the occurrence of acute unclassified leukemia.     

CD19-positive acute myeloblastic leukemia developed 12 years after the onset of hypereosinophilic syndrome

We report a rare case of hypereosinophilic syndrome (HES) that developed to acute myeloblastic leukemia (AML). The patient, a 34-year-old man, presented with eosinophilia of unknown origin (white blood cells 38,200/microliter with 74% eosinophils) and pericardial effusion, and was diagnosed as having HES with a normal karyotype. He received four cycles of combination chemotherapy including cyclophosphamide, cytosine arabinoside and vindesine, and thereafter remained in remission. After 12 years, he was referred to our hospital because of fever and malaise. On admission, CBC showed white blood cells 3,000/microliter with 70% myeloblasts and 3% eosinophils. The bone marrow was hypercellular with 95% blasts, which were negative for myeloperoxidase (MPO) staining. Immunophenotype analysis revealed that the cells were positive for CD13, CD19, CD34, HLA-DR and cytoplasmic MPO. CD19-positive AML was diagnosed. Cytogenetic analysis showed 46, XY, t(6;21)(q13;q22), add(7)(q11) in 19 of 20 metaphase spreads. Rearrangement of the AML1 gene at 21q22 and fusion of the BCR/ABL gene could not be detected by fluorescence in situ hybridization analysis. The patient received combination chemotherapy and achieved a complete remission. Chromosome aberrations involving 7q as well as 21q22 suggested that the initial chemotherapy for HES might have been implicated in the pathogenesis of acute leukemia in this case.     

Non-specific esterase positive neutrophils in a case of refractory anemia with excess of blasts

A 61-year-old woman was admitted with complaint of fever. The peripheral blood showed pancytopenia and bone marrow aspirate showed dysplasia in trilineage blood cells with increased blasts (18.2%). Bone marrow chromosome study revealed a karyotype of 46XX, -6, 3q-, +mar in 19 cells of 20 analyzed. She was diagnosed as refractory anemia with excess of blasts (RAEB). 95% of neutrophils in the bone marrow and 84% of that in the peripheral blood were stained with non-specific esterase using alpha-naphthyl acetate as substrate. On the other hand, the positivity of neutrophils for peroxidase. Sudan black B or chloroacetate esterase was markedly decreased. The phagocytotic activity of neutrophils was increased in comparison with normal control cells. Surface marker analysis of peripheral blood myeloid cells revealed increased expression of monocyte specific markers. These findings suggested that the patient's neutrophils, which were surely neutrophils in morphology, shared also monocyte-specific characters. After treatment with low dose Ara-C, pancytopenia was recovered and blasts in the bone marrow were reduced. Also was decreased non-specific esterase positive neutrophils, indicating that the neutrophils were derived from abnormal myeloid clone.     

Loeys-Dietz syndrome with acute myeloid leukemia

A 54-year-old man, who had been diagnosed with Loeys-Dietz syndrome based on his past history, family history, clinical findings, and the presence of a gene mutation, was referred to our hospital because of easy fatigability. Anemia, thrombocytopenia, and blasts in his peripheral blood were noted, and 31.4% blasts were found in a bone marrow aspiration. The blasts were positive for myeloperoxidase and esterase staining. Furthermore, karyotype analysis of bone marrow cells showed t(11;19)(q23;p13.1) and MLL abnormality was detected on RT-PCR A diagnosis of acute myeloid leukemia (M4) with 11q23 (MLL) abnormality was made. Loeys-Dietz syndrome is a Marfan-like congenital connective tissue disorder caused by a heterozygous missense mutation of a TGF-beta receptor I or II gene. The TGF-beta family inhibits the proliferation of normal epithelial cells and induces apoptosis, and is therefore known as a tumor suppressor factor. In this article, we discussed the association between Loeys-Dietz syndrome with a TGF-beta receptor gene mutation and cancer.     

Ph1 positive acute lymphoblastic leukemia with DIC after operation of colon and lung cancer

We reported a rare case of triple cancers with acute lymphoblastic leukemia (ALL) associated with disseminated intravascular coagulopathy (DIC) after the operations of colon cancer and primary lung cancer. A 78-year-old Japanese male, who had been operated upon for colon cancer (adenocarcinoma) on March 1981, metastatic brain tumor (adenocarcinoma) on December 1986, and primary lung cancer (squamous cell carcinoma) on February 1987, was admitted to our hospital because of severe general malaise on December 6 1987. On admission, he had mild hepatosplenomegaly and hemorrhage diathesis such as purpura. Serum LDH increased to 2,515 mU/ml. The white blood cell count was 6,210/microliters with 53% leukemia cells, and the platelet count was 12,000/microliters. A bone marrow was infiltrated with 96.0% leukemia cells. The leukemia cells stained positively for PAS and negatively for peroxidase. Immunological examination of leukemia cells showed that HLA-DR, TdT, B1 and J5 were positive and cytoplasmic Igmu and surface Ig were negative, indicating common ALL. The coagulation studies revealed that the activated partial thromboplastin time was prolonged to 42.0 seconds, FDP increased to 79.9 micrograms/ml, and antithrombin-III decreased to 62%. Chromosome analysis showed a 48, XY, +2, +21q-, t(9;22) karyotype. He was diagnosed as having Ph1 positive ALL associated with DIC. He was treated with vindesine, prednisolone, L-asparaginase, and adriamycin and complete remission (CR) was achieved after two months. But on August 1988, 8 months after CR, ALL and brain tumor relapsed and he died of pneumonia on September 19, 1988.     

Prominent lymphadenopathy and double Ph1 chromosomes as initial and recurrent manifestations of chronic myelogenous leukemia in blast crisis: report of a case and review of the literature

A 60-year-old woman was admitted because of fatigue. Physical examination revealed prominent peripheral lymphadenopathy, marked tonsillar swelling and hepatosplenomegaly. The leukocyte count was 68,900/microliters with 75% lymphoid blasts and 5% basophils. The karyotype of the blood cells was 46, XX, Ph1/47, XX, Ph1, +Ph1. The diagnosis of CML in blast crisis was made. After chemotherapy using adriamycin, cyclophosphamide, vincristine, and prednisolone (CHOP), lymphadenopathy and splenomegaly reduced and lymphoid blasts disappeared from the blood and bone marrow. At that time only single Ph1 (46, XX, Ph1) clone was detected in her bone marrow. Four months later, hematological relapse accompanied by lymphadenopathy occurred and DNA analysis of the blasts showed the rearrangement of bcr gene. The simultaneous chromosomal analyses of the blood, bone marrow and lymph node revealed that almost all cells examined had the karyotype "47, XX, Ph1, + Ph1". In spite of repeated chemotherapy the patient did not improve and died. This case suggests a relationship between lymphadenopathy and double Ph1 chromosomes in CML.     

Acute myelomegakaryocytic leukemia developed from myelodysplastic syndrome after chemotherapy against complicated small cell lung cancer]

A patient with acute myelomegakaryocytic leukemia (AMMgL), which developed from myelodysplastic syndrome (MDS) after chemotherapy against complicated small cell lung cancer, is reported. The patient was a 66 year-old male, who first presented with moderate macrocytic anemia. Bone marrow aspiration showed absolute erythroid hypoplasia and morphological abnormalities were found in erythroid, granuloid and megakaryocytic lineage cells. Iron utilization studies using radioisotope showed ineffective hematopoiesis. He was diagnosed as having MDS (refractory anemia) and treated with prednisolone, fluoxymesterone, and transfusions. After 3 years, small cell lung cancer was found, but he achieved complete remission with chemotherapy. Since then, pancytopenia progressed with myelofibrosis. Abnormal blasts were found in peripheral blood and gradually increased. He finally died from a blastic crisis resulting in gastric bleeding. The blasts were peroxidase negative, platelet peroxidase positive (10%), and glycoprotein II b/III a antibody positive, indicating megakaryoblasts.