Coexisting primary tumors from esophageal cancer and myelodysplastic syndromes: A case report.

This is the first report of the double primary cancer of esophageal cancer (EC) and myelodysplastic syndromes (MDS) treated without esophagectomy. Previously reported cases of the double cancer mostly describe secondary MDS arising after treatment for EC. The double primary cancer was manageable with close follow-ups for possible recurrence.

Dramatic response of chemotherapy for cancer of unknown primary origin of sarcomatoid carcinoma producing granulocyte colony-stimulating factor.

Cancer of unknown primary origin (CUP) which is usually diagnosed based on the histological type of metastatic site has marked heterogeneous characteristics. Sarcomatoid carcinoma defined as CUP has not been reported according to our literature survey. A 59-year-old man presented with enlarged multiple thoracic lymph nodes, huge splenomegaly and nodules in left temporal lobe of the brain. The histopathological diagnosis of lymph node and spleen was sarcomatoid carcinoma. However, all extensive diagnostic examinations could not detect a site of primary origin. The laboratory data showed marked leukocytosis with increased serum granulocyte colony-stimulating factor (G-CSF). Therefore, the patient was finally diagnosed of CUP of sarcomatoid carcinoma producing G-CSF. After gamma knife treatment for brain metastases, two regimens of taxan-based chemotherapy (carboplatin and paclitaxel, gemcitabine and docetaxel) were administered, with no effect but further tumor progression. Splenectomy for avoiding splenic rupture was performed. As the third line chemotherapy, the combination consisting of doxorubicin and ifosfamide was administered and showed a good therapeutic effect and normalized white blood cell count and serum G-CSF level. He achieved complete remission after three cycles. Herein we present an extremely rare case of CUP of sarcomatoid carcinoma producing G-CSF. Our case suggests the importance of chemotherapy including doxorubicin and ifosfamide, and multimodal therapeutic strategy for this aggressive disease.

[Development of chronic myelogenous leukemia during treatment with TPO receptor agonist for ITP].

We report a 77-year-old Japanese man with idiopathic thrombocytopenic purpura (ITP) which developed into chronic myelogenous leukemia (CML) during treatment with eltrombopag, a thrombopoetin (TPO) receptor agonist, because the disease was refractory to prednisolone. Eltrombopag can induce a good reaction in terms of the platelet count. However, CML in the chronic phase developed in about 19 months in our present case. Dasatinib was administered because he had diabetes. However, a blastic crisis immediately occurred. He died despite switching to Nilotinib. Recently, the occurrence of myelofibrosis and hematological malignancies due to long-term use of TPO receptor agonists has become a concern. This is the first report of a TPO receptor agonist possibly contributing to CML onset and crisis.

Tumour-associated macrophages in diffuse large B-cell lymphoma: a study of the Osaka Lymphoma Study Group.

AIMS: To evaluate the role of tumour-associated macrophages (TAMs) of the M1 and M2 types in the behaviour of diffuse large B-cell lymphoma (DLBCL). METHODS AND RESULTS: Double immunohistochemical staining of HLA-DR/CD68 (M1) or CD163/CD68 (M2) was performed in 101 cases of DLBCL. CD68+ cells represent the total number of TAMs. The average number of double-positive cells was counted, and the cut-off value was set at the mean number of counts, i.e. 30.7 and 27.0 for M1 TAMs and M2 TAMs, respectively. That for total TAMs was set at the 90th percentile number of total counts, i.e. 132.3. Cases were categorized into three pairs: high (34 cases) and low (67 cases) M1 TAM groups, high (39 cases) and low (62 cases) M2 TAM groups, and high (10 cases) and low (91 cases) total TAM groups. The difference in overall survival rates was statistically significant between the high and low M2 TAM groups (P < 0.01) and between the high and low total TAM groups (P < 0.05). Multivariate analysis revealed that the presence of a bulky mass and a higher number of M2 TAMs were significant factors for poor prognosis (P < 0.05). CONCLUSIONS: Estimation of specific type of macrophages, of the M1 and M2 types, is superior to the estimation of TAMs as a whole (CD68+ cells) for prediction of the prognosis of DLBCL patients.

[Definitive diagnosis of intravascular large B-cell lymphoma by random skin biopsy].

A 69-year-old male was admitted to our hospital for high-grade-fever and body weight loss lasting for a few months. In a previous hospital, extensive laboratory examinations and imaging modalities had failed to establish the origin of the fever. On admission he showed mild anemia, and elevated LDH and CRP, together with a high sIL-2R level, suggesting a possibility of lymphoid malignancy without nodal or solid organ involvements, in particular, intravascular large B-cell lymphoma(IVLBCL). A bone marrow biopsy revealed no abnormal findings except minimal hemophagocytosis. A random skin biopsy was then performed, though no detectable skin lesion was seen. The histological results of the skin materials clearly showed a prominent intravascular large lymphoid cell proliferation with a phenotype of CD20+, CD79a+, CD3- and CD5- in the small vessels. On the basis of these findings, a diagnosis of IVLBCL was established and the patient was treated with(R-)CHOP regimen immediately, which resulted in complete remission following two courses of chemotherapy. Difficulties often arise in the diagnosis of IVLBCL when suspicious lesions suitable for biopsy are lacking. Random skin biopsy would therefore be a useful tool if less invasive measures fail.

[A case of chronic myeloid leukemia occurring during treatment for chronic lymphocytic leukemia].

Since the progression of chronic lymphocytic leukemia(CLL)is long and requires lengthy primary disease management, the risk of double primary cancers and secondary cancer due to treatment has become an issue in western countries with a high incidence of CLL. However, the coexistence with chronic myeloid leukemia(CML)is rare even in the West, and no cases have been reported in Japan. At this time, we would like to report a rare case of CML coexisting during the progression of CLL. The patient was a 68-year-old woman. As she had entered the advanced stage of B-cell chronic lymphocytic leukemia(B-CLL), fludarabine, a purine analog agent, was administered. Two years later, a high-granulocyte dominant white blood cell count began to appear. BCR/ABL analysis by FISH was 97. 6%positive, and the chromosomal test was t(9:22)(q34:q11), so CML was diagnosed. Coexistence of CML in CLL can mainly be classified into three types; CML preceding CLL, CLL preceding CML, and simultaneous occurrence, and the most common, as in this case, long progression CLL preceding CML. At this time, we performed a mainly bibliographical consideration according to the main occurrence type, including the possibility of secondary CML due to fludarabine.

Molecular basis of clonal expansion of hematopoiesis in 2 patients with paroxysmal nocturnal hemoglobinuria (PNH).

Somatic mutation of PIGA in hematopoietic stem cells causes deficiency of glycosyl phosphatidylinositol-anchored proteins in paroxysmal nocturnal hemoglobinuria (PNH) that underlies the intravascular hemolysis but does not account for expansion of the PNH clone. Immune mechanisms may mediate clonal selection but appear insufficient to account for the clonal dominance necessary for PNH to become clinically apparent. Herein, we report 2 patients with PNH whose PIGA-mutant cells had a concurrent, acquired rearrangement of chromosome 12. In both cases, der(12) had a break within the 3' untranslated region of HMGA2, the architectural transcription factor gene deregulated in many benign mesenchymal tumors, that caused ectopic expression of HMGA2 in the bone marrow. These observations suggest that aberrant HMGA2 expression, in concert with mutant PIGA, accounts for clonal hematopoiesis in these 2 patients and suggest the concept of PNH as a benign tumor of the bone marrow.

Long-term support of hematopoiesis by a single stem cell clone in patients with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder characterized by clonal blood cells that are deficient in glycosylphosphatidylinositol-anchored proteins because of somatic mutations of the PIG-A gene. Many patients with PNH have more than one PNH clone, but it is unclear whether a single PNH clone remains dominant or minor clones eventually become dominant. Furthermore, it is unknown how many hematopoietic stem cells (HSCs) sustain hematopoiesis and how long a single HSC can support hematopoiesis in humans. To understand dynamics of HSCs, we reanalyzed the PIG-A gene mutations in 9 patients 6 to 10 years after the previous analyses. The proportion of affected peripheral blood polymorphonuclear cells (PMNs) in each patient was highly variable; it increased in 2 (from 50% and 65% to 98% and 97%, respectively), was stable in 4 (changed less than 20%), and diminished in 3 (94%, 99%, and 98% to 33%, 57%, and 43%, respectively) patients. The complexity of these results reflects the high variability of the clinical course of PNH. In all patients, the previously predominant clone was still present and dominant. Therefore, one stem cell clone can sustain hematopoiesis for 6 to 10 years in patients with PNH. Two patients whose affected PMNs decreased because of a decline of the predominant PNH clone and who have been followed up for 24 and 31 years now have an aplastic condition, suggesting that aplasia is a terminal feature of PNH.