A 66-year-old woman was admitted to our hospital, because of a prolonged fever of unknown origin with a 5-week duration and general fatigue. No antibiotics were effective. She had a previous history of breast carcinoma; stage I, treated by only mastectomy without any adjunct chemotherapy or radiotherapy at 44 years old. On admission, she had high-grade fever; 39C, pulse was 110 bpm and regular, and blood pressure was 125/75 mmHg. Physical examination revealed petechiae in the trunk and bilateral extremities, but neither lymphadenopathy, splenomegaly nor skin eruptions were present. Blood tests on admission showed the following: white blood cell (WBC) count 4100/microl (band+seg 78.0 %, mono 10.0 %, lymph 12.0 %); hemoglobin (Hgb) 11.0 g/dl; platelet count (Plt) 1.6 x 104/microl; lactate dehydrogenase (LDH) 735 IU/l (normal range 124-222 U/L); AST 121 IU/L; ALT 86 IU/l; total bilirubin (T-Bil) 0.44 mg/dl; triglyceride (TG) 200 mg/dl; C-reactive protein (CRP) 8.81 mg/dl; ferritin 1,150 ng/ml; and soluble interleukin-2 receptor (sIL2-R) 13,100 U/ml (Table 1). Routine tests including blood coagulation profile, kidney functions, serum iron, vitamin B12, folic acid, and haptoglobin revealed normal. Tests for tuberculosis and viruses including hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and cytomegalovirus (CMV) were negative. Epstein-Barr (EBV)-VCA IgG was 640x, EBV-VCA IgM was > 10x, and EBV-EBNA was 10x >, but the EBV DNA titer was within normal limits. Protein and immunoelectrophoresis, immunoglobulin, C3, C4 complement, anti-nuclear antibodies (ANA), lupus anticoagulant (LA), rheumatoid factor (RF), and thyroid function were normal or negative. Repeated blood cultures were also normal. A cervical, chest, abdominal and pelvic computed tomography (CT) scan and Gallium scintigraphy revealed no lymphadenopathy, hepatosplenomegaly or other abnormal findings. In contrast, bone marrow aspiration demonstrated widespread infiltration of medium to large sized atypical lymphoma cells with distinct nucleoli, basophilic cytoplasm, and cytoplasmic vacuoles, whose immunophenotyping revealed CD5-/CD10-/CD19+/CD20+/Igkappa+ (Fig. 1(a): May-Giemsa stain x1000, Fig. 1(b): Immunophenotyping panel). The number of megakaryocyte was decreased. Bone marrow biopsy consistently revealed hypercellularity with widespread infiltration of large lymphoma cells positive for CD20 (L26), CD79alpha, BCL6, BCL2, MUM1, but negative for CD3 (Fig. 1, c: hematoxylin and eosin x200, d: CD20 x200, e: CD79alphax200, f: BCL6 x400, g: BCL2 x400, h: MUM1 x400, i: CD3 x200). Pathologically, the proliferation of large lymphoma cells on the lumina of small vessels were not detected. In addition, EBV encoded small RNA (EBER) in situ hybridization was not detected on bone marrow tissues. Immunohistochemical analysis showed that these cells were negative for MPO, glycophorin C, CD34, c-kit, and terminal deoxyribonucleotidyl transferase (TdT). Cytogenetic analysis of the bone marrow cells demonstrated that 15 of the 20 cells analyzed showed complex chromosomal abnormalities; 47, XX, -1, add (3) (q11.2), add (4) (q31), t(6;14) (p21;q32), del (8) (q22q23), ?t(9;14) (p13b;q32), add(12)(p11.2), der(12)add(12)(p13), add (12) (q22), der(15)t(1;15) (q11;p11.1)del(1)(q23q25), der (16)add(16)(p11.2)add(16)(q22), +18, add(20) (q11.2), +der(?)t(?;1)(?;p22) (Fig. 1(j)). Based on these results, the patient was diagnosed as having PBML/DLBCL, non-germinal center B cell like (non-GCB type); stage IVB (Age-adjusted International Prognostic Index: IPI score; high risk) and was immediately treated with R-CHOP chemotherapy (rituximab; 375 mg/m2; day 1, cyclophosphamide; 750 mg/m2; day 2, doxorubicin; 50 mg/m2; day 2, vincristine 1.4 mg/m2; day 2, prednisolone; 100 mg/body day 1 - day 5). She attained complete bone marrow response with no evidence of residual lymphoma cells in the bone marrow, assessed by immunohistochemistry on day 28 of the first cycle of the chemotherapy (Table 1, Fig. 2(a): hematoxylin and Eosin x200, b: CD20 x200) and chromosomal analysis showed normal karyotype (Fig. 2(c)). She had a normal platelet level of 21.7x104/microl. The level of LDH was 114 IU/l and sIL2-R was also decreased to 1470 U/ml. Baseline cerebrospinal fluid (CSF) examination was clear of atypical lymphoma cells, but prophylactic intrathecal methotrexate was given. She has remained in CR after receiving total 8 courses of R-CHOP chemotherapy. However, she had a prolonged low-grade fever, so she continued to be treated with moderate doses of prednisolone. After 6 cycle of R-CHOP chemotherapy, prednisolone was discontinued, and she has remained free of fever. During the clinical course, she suffered from a varicella zoster virus (VZV) infection once, but this was immediately resolved by the administration of aciclovir. She had moderate osteoporosis due to prednisolone treatment and continue to take regular check-up at orthopedic surgery in our hospital.
Currently, 8 years after the initial presentation, the patient has no signs of recurrence of lymphoma on the bone marrow survey including chromosomal analysis (Fig. 2(d)). Positron emission tomography (PET)/CT scan revealed slightly low 18F-FDG up-take which is considered to be associated with osteoporosis (Fig. 2(e)). She works every day, as she had before the diagnosis of lymphoma (Table 1).