Takahiro Nagashima^1,2, Kazuo Muroi^1,2, Masae Kunitama¹, Tohru Izumi¹, Tetsuya Ohtsuki¹, Norio Komatsu¹, Masashi Fukayama³ and Keiya Ozawa

¹Division of Hematology, Department of Medicine, ²Division of Cell Transplantation and Transfusion and ³Department of Pathology, Jichi Medical School, Tochigi, Japan

A 59-year-old man was admitted to our hospital because of disturbance of consciousness and hyponatremia. The patient had suffered from acute myelogenous leukemia (AML) with 46,XY and received chemotherapy for 5 years. Meningeal carcinomatosis was diagnosed due to the detection of carcinoma cells in the cerebrospinal fluid (CSF). Hyponatremia was caused by syndrome of inappropriate secretion of anti-diuretic hormone (SIADH). Bone marrow examination revealed myelodysplastic syndrome (MDS) with deletion of the long arm of chromosome 7. Emergence of a new abnormal clone was suggested. The patient died from brain herniation. Post mortem examination showed adenocarcinoma in the colon. An association between chemotherapy and both colon cancer and MDS was suggested.

Introduction
Second neoplasms are known to be early and late complications in patients with leukemias and lymphomas following chemotherapy and irradiation. The use of alkylating agents and topoisomerase 2 inhibitors is associated with the development of therapy-related myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) (1–4). In contrast, the risk of developing therapy-related solid tumors is associated mainly with the use of radiation therapy in patients with Hodgkin’s disease (5). We present here a unique case of second neoplasms in which the patient had received chemotherapy to treat AML for 5 years and subsequently developed colon cancer with meningeal carcinomatosis and MDS simultaneously.

Case Report

A 55-year-old man was admitted to the Jichi Medical School Hospital because of fatigue and bleeding tendency in January 1993. He was diagnosed as having AML (FAB classification, AML-M4). Chromosome analysis of bone marrow cells showed 46,XY (30/30 cells). After induction chemotherapy by the JALSG–AML92 protocol (enocitabine, etoposide, daunorubicin and 6-mercaptopurine) (6), he achieved complete remission. He was then treated with three courses of consolidation chemotherapy (first course, mitoxantrone and cytarabine; second, enocitabine, etoposide, daunorubicin and 6-mercaptopurine; third, enocitabine and aclarubicin), until November 1993, but the treatment was complicated by severe bacterial sepsis and cellulitis. To prevent severe infection due to intensive chemotherapy-induced neutropenia, his treatment was continued with low-dose chemotherapy including cytarabine, 6-mercaptopurine, cytarabine ocfosfate and etoposide monthly until April 1998. The cumulative dose of etoposide was 4870 mg. In September 1996, bone marrow aspiration had revealed complete remission with normal karyotype (9/9 cells).

In May 1998, he experienced nausea, general fatigue and tarry stool. Therefore, he visited his local physician. Peripheral blood analysis showed a normal blood cell count. The serum sodium concentration was 127 mmol/l and the levels of thyroid hormones, aldosterone and cortisol were normal. The results of fiberscopic examination of the upper gastrointestinal tract were normal. His consciousness gradually deteriorated. Computed tomography (CT) of the patient’s head showed no bleeding, infarction or tumors. He was transferred to our hospital on June 3, 1998.

Physical examination showed no lymphadenopathy or hepatosplenomegaly. Neurological examination revealed stiff neck. Peripheral blood showed a white blood cell count of 6800/µl with 8% stab, 76% segment, 3% monocytes and 13% lymphocytes, a hemoglobin concentration of 12.1 g/dl and a platelet count of 13.0 x 10⁴/µl. Serum lactate dehydrogenase (LDH) level was normal but carcinoembryonic antigen (CEA) and CA19-9 levels were markedly elevated (1613 ng/ml and 43 820 U/ml, respectively). Serum sodium concentration was low (121 mmol/l) and both serum and plasma osmolarity were low (240 and 243 mOsm, respectively). Serum creatinine level was normal. Urinalysis showed a high specific gravity (1.042) and hyperosmolarity (779 mOsm). Taken together with serum and urine data, diagnosis of syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) was made.

On June 4, he received lumbar puncture to rule out meningeal infiltration of leukemic cells. The cerebrospinal fluid (CSF) revealed monocytic pleocytosis, high protein and low sugar concentrations and increased levels of LDH (967 IU/l) and CEA (4820 ng/ml). Cytospin preparations showed large atypical mononuclear cells, which had abundant and basophilic cytoplasm without granules. Nuclei were round and eccentrically placed with nucleoli (Fig. 1A). The periodic acid–Schiff (PAS) reaction was strongly positive (Fig. 1B). Gadolinium-enhanced magnetic resonance imaging (MRI) of the brain showed linear enhancement of the leptomeninges and enlargement of the cerebral ventricles. The patient was diagnosed as having meningeal carcinomatosis. Results of CT of the chest and ultrasonography of the abdomen were normal. Bone marrow aspiration revealed no proliferation of blasts and mild cellular atypism in neutrophils, erythroblasts and megakaryocytes (Fig. 2). Chromosomal analysis of bone marrow cells revealed deletion of the long arm of chromosome 7 (9/30 cells). He was diagnosed as having MDS.