Japanese Journal of Clinical Oncology 31:221-225 (2001)
© 2001 Foundation for Promotion of Cancer Research
Colon Cancer with Meningeal Carcinomatosis and Myelodysplastic Syndrome in a Patient Who Underwent Intensive Chemotherapy for Acute Myelogenous Leukemia: a Case Report
1Division of Hematology, Department of Medicine, 2Division of Cell Transplantation and Transfusion and 3Department of Pathology, Jichi Medical School, Tochigi, Japan
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ABSTRACT |
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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.
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INTRODUCTION |
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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.
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CASE REPORT |
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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.
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Although his consciousness improved following correction of the serum sodium concentration, it suddenly deteriorated and right hemiplegia occurred on June 15. MRI of the brain demonstrated progression of enlargement of the cerebral ventricles. The administration of mannitol and dexamethasone caused a transient improvement of his consciousness, but he died on June 21, 1998.
Post mortem examination showed a tumor, 4.5 x 5cm in size, histologically demonstrated to be a poorly differentiated adenocarcinoma, at the hepatic flexure in the ascending colon (Fig. 3). The cancer cells had abundant cytoplasm and formed alveolar structures and showed loose cell–cell connection. They had mucin in their cytoplasm, which stained positively with alcian blue and PAS. The cells were immunohistochemically negative for chromogranins or synaptophysin. Some cells had infiltrated into the stroma with prominent vascular permeation (Fig. 3). Numerous nodules of carcinoma cells were seen in the abdominal cavity. The leptomeninges showed diffuse infiltration by carcinoma cells including the posterior lobe of the pituitary gland (Fig. 4). The proliferation of leukemic blasts was not identified in any of the organs, including the bone marrow.
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DISCUSSION |
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We have described a case of double primary cancers, colon cancer and MDS, as second neoplasms. Second neoplasms are an important late complication following chemotherapy and irradiation in patients with non-Hodgkin’s lymphoma, Hodgkin’s disease, AML and other malignancies (1–5,7–10). Multiple-organ simultaneous primary cancers occur less frequently and we could not find similar cases.
Krause et al. reported that 26 of 2262 patients (1.14%) developed secondary solid tumors following primary aggressive treatment of hematological malignancy (11). Most of the second neoplasms were lung (26.9%), colon (23.1%) or gastric cancers (15.4%). Elderly patients developed second neoplasms (20%) more frequently than younger patients (9.2%) (12). Nagura and Kawashima reported that secondary solid tumors included gastric, lung and head and neck cancer, and 90 of 101 patients with second neoplasms had received chemotherapy or radiotherapy (13). Niitsu and Umeda reported that 56 of 674 patients (8.3%) with hematological malignancies developed solid tumors (14). Bhatia et al. reported that in the recipients of bone marrow transplantation, 17 of 2150 patients (0.79%) developed solid tumors such as malignant melanoma, brain tumors and basal cell carcinoma (15). The cumulative probability of solid tumors in the 2150 patients was 5.6% at 13 years, with a sharp increase after 8 years. In multivariate analysis, total-body irradiation was associated with an increased risk of developing solid tumors (5,7).
Alkylating agents and topoisomerase 2 inhibitors are known to be associated with AML, MDS and solid tumors (1–4,13, 16–18). In alkylating agent-related secondary hematological disorders, deletions in chromosome 5 or 7 are frequently seen (3,19,20), while in those associated with topoisomerase 2 inhibitors, 11q23 abnormalities have been detected (1). Our patient was treated with topoisomerase 2 inhibitors but not alkylating agents, although aberration of chromosome 7 was detected in bone marrow cells. Chromosomal abnormalities were not detected at the initial presentation or at complete remission in leukemia. Since he received chemotherapy including a total of 4870 mg of etoposide, the chemotherapeutic agent may have contributed to the development of both colon cancer and MDS.
Meningeal carcinomatosis occurs in 1–15% of patients with solid tumors (21) and is characterized by three major symptoms: cerebral, cranial nerve and spinal root symptoms (22–26). Headache is the most common symptom, seen in one third of patients at initial presentation (27). Our patient had a cerebral symptom, i.e. disturbance of consciousness, on admission. Primary tumors in meningeal carcinomatosis differ between Japan and Europe or the USA. In Japan, gastric (56.2%), lung (32%), thyroid (2.3%), breast (1.2%) and colon cancer (1.2%) are frequently encountered, whereas in Europe and the USA the frequencies of gastric (36.8%) and lung cancer (25%) are lower, but those of breast (11.1%) and colon cancer (5.6%) are relatively high (28). The single most helpful test in diagnosing meningeal carcinomatosis is examination of CSF obtained by lumbar puncture. Usually, CSF shows elevated protein and decreased glucose levels and definitive diagnosis is made by the detection of cancer cells in CSF. Elevation of CEA in CSF in patients with meningeal carcinomatosis has been reported (29). CT and gadolinium-enhanced MRI are also useful for diagnosing meningeal carcinomatosis (30,31). In our patient, a diagnosis of meningeal carcinomatosis was made by CSF and cytological analyses. Brain MRI was also helpful for diagnosis.
Our patient had hyponatremia due to SIADH. SIADH in our patient was caused by local metastasis from colon cancer to the pituitary gland. SIADH is usually caused by malignant neoplasms with autonomous vasopressin release, non-malignant pulmonary diseases, central nervous disorders and drugs (32). There have been only a few reports of patients with both meningeal carcinomatosis and SIADH (33).
We have reported a case of colon cancer with meningeal carcinomatosis and MDS in which the patient had received chemotherapy. It seems likely that colon cancer and MDS were related to chemotherapy including etoposide. We should pay attention not only to MDS but also to the development of solid tumors following chemotherapy in AML patients.
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FOOTNOTES |
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+ For reprints and all correspondence: Takahiro Nagashima, Division of Cell Transplantation and Transfusion, Jichi Medical School, 3311–1 Yakushiji, Minamikawachi-Machi, Kawachi-Gun, Tochigi 329-0498, Japan. E-mail: tnag@jichi.ac.jp
Abbreviations: AML, acute myelogenous leukemia; CSF, cerebrospinal fluid; SIADH, syndrome of inappropriate secretion of anti-diuretic hormone; MDS, myelodysplastic syndrome; CT, computed tomography; LDH, lactate dehydrogenase; CEA, carcinoembryonic antigen; PAS, periodic acid–Schiff; MRI, magnetic resonance imaging
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REFERENCES |
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Received November 24, 2000; accepted January 26, 2001.
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