A 73-year-old man visited an outpatient clinic because of poor appetite, progressive bilateral lower leg weakness, and low-grade fever, especially in afternoons, for 2 months. No significant travel or cluster or contact history was reported. His medications were for control of hypertension, type 2 diabetes mellitus, dyslipidemia, peripheral artery occlusive disease, and an old cerebrovascular accident.
On physical examination, his temperature was 38.2 C, blood pressure was 98/51 mmHg, and pulse was 108 beats per minute. He had decreased muscle power (score 4 out of 5) over his bilateral lower legs and a palpable liver (5 cm below the right subcostal border). No heart murmur, palpable spleen, or lymphadenopathy was noted.
After admission, laboratory data revealed normocytic anemia, thrombocytopenia, mild cholestasis, and elevated lactate dehydrogenase (LDH; the results were shown in Table 1 in detail). Furthermore, extensive septic workup for fever of an unknown origin was completed, including chest X-ray, sputum acid-fast stain, serum tuberculosis polymerase chain reaction, blood culture, serum anti-HIV test, and echocardiography. All above tests were negative. Due to the anemia and reverse albumin/globulin ratio, serum immunofixation electrophoresis was checked and revealed a thin band of IgM/kappa monoclonal gammopathy. Furthermore, serum beta-2 microglobulin levels were elevated to 7.75 mg/L. As a result, a hematologist was consulted and a bone marrow study was performed. Bone marrow smear showed severe hemophagocytosis (Figure 1) and no abnormal population or light chain restriction indicated by flow cytometry. Serum tests revealed hypertriglyceridemia and hyperferritinemia. Abdominal ultrasonography also showed marked splenomegaly (splenic index: 6.9 cm x 5.1 cm). Hemophagocytic syndrome (HPS) was confirmed, but the etiology was still unclear.
Moreover, abdominal ultrasonography disclosed multiple hypoechoic lesions up to 2 cm on both lobes (Figure 2(a)). However, the viral hepatitis profile was negative for hepatitis B or C infection. Tumor markers, including alpha-fetoprotein, carcinoembryonic antigen, carbohydrate antigen 19-9, squamous cell carcinoma antigen, and prostatic specific antigen, were all within normal range. Abdominal computed tomography (CT) showed multiple ill-defined poor enhancing nodular lesions on both hepatic lobes (Figure 2(b)). However, esophagogastroduodenoscopy and colonoscopy showed no evidence of gastrointestinal malignancy. Because the nature of multiple liver tumors was inconclusive, we performed a liver biopsy. Microscopic examination of the liver biopsy showed diffuse large B cell lymphoma (Figure 2(c)), identifying lymphoma cells CD20+/CD10-/BCL-6+/BCL-2+/cyclin D1-/EBER- (Figure 2(d)). Because of old age, multiple comorbidities, and the fragile clinical status of the present case, we initiated chemotherapy with rituximab and bendamustine (rituximab 375 mg/m2 for 1 day; bendamustine 90 mg/m2 for 2 days). After the first cycle of chemotherapy, follow-up laboratory data showed dramatic improvement of anemia, thrombocytopenia, hyperbilirubinemia, and hemophagocytosis indices, including triglyceride and ferritin levels (Table 1). After the second cycle of chemotherapy, abdominal CT revealed excellent treatment response with much smaller hypovascular lesions at both hepatic lobes compared with the prior study (Figure 3). However, a persistent fever occurred 1 month after finishing the total six cycles of chemotherapy with rituximab and bendamustine. Lym-phoma relapse was highly suspected. However, whole body positron emission tomography-computed tomography (PET-CT) showed no evidence of lymphoma recurrence. Repeated bone marrow study disclosed residual hemophagocytosis. Steroid therapy with methylprednisolone was administered and the fever subsided. Further-more, the patient's general condition gradually improved. Unfortunately, 3 months after the last cycle of chemotherapy with rituximab and bendamustine, a follow-up bone marrow study revealed aggregations of abnormal lymphoid cells, compatible with lymphoma with marrow involvement. As a result, treatment was switched to R-mini-CHOP (rituximab 375 mg/m2 for 1 day, cyclophosphamide 400 mg/m2 for 1 day, doxorubicin 25 mg/m2 for 1 day, vincristine 1 mg/day for 1 day, and prednisolone 30 mg/day for 5 days), but a poor response was noted. The patient then received two cycles of R-EPOCH (rituximab 375 mg/m2 for 1 day, etoposide 50 mg/m2 for 4 days, cyclophosphamide 750 mg/m2 for 1 day, doxorubicin 10 mg/m2 for 4 days, vincristine 0.5 mg/day for 4 days, and prednisolone 30 mg/day for 5 days). A follow-up bone marrow study still showed residual lymphoma cells and hemophagocytosis. The disease was thereafter resistant to chemotherapy, after which the patient finally died of severe Klebsiella pneumoniae infection.