Tomoko Nagai

Hemophagocytic syndrome in elderly patients with underlying autoimmune diseases.

In patients with autoimmune disease-associated hemophagocytic syndrome (AAHS), the clinical features may differ from hemophagocytic syndrome (HPS) of other etiologies, and new criteria for AAHS have been proposed. Since bone marrow (BM) circumstances are changed according to aging, here we reviewed retrospectively our cases with AAHS in elderly patients, including two systemic lupus erythematosus (SLE), three Evans syndrome, one rheumatoid arthritis (RA), one Hashimoto thyroiditis, and one autoimmune pancreatitis. Although only two SLE patients were diagnosed as HPS by the classical criteria, the remaining patients except one RA met the criteria for AAHS. Seven patients except one SLE patient showed good response to therapy and demonstrated positive autoantibodies to blood cells, lower serum ferritin levels, and increased erythroblastic islands in the BM. We consider the diagnosis of AAHS should be carefully made when macrophages phagocytosing blood cells are observed in BM smear without hyperferritinemia in elderly patients with autoimmune diseases.

Low dose cepharanthine ameliorates immune thrombocytopenic purpura associated with multiple myeloma

Immune thrombocytopenic purpura associated with multiple myeloma is extremely rare. Here, we present the successful management of an elderly Japanese patient with multiple myeloma complicated by immune thrombocytopenia with low dose cepharanthine - a plant derived alkaloid. A 78-year-old male patient with IgGκ multiple myeloma was repetitively treated with melpharan and prednisolone. In each chemotherapy course, we demonstrated a close relationship between platelet recovery and administration of high dose prednisolone. When further chemotherapy was avoided because of the patients poor general condition, administration of cepharanthine was effective in halting progressive thrombocytopenia due to abnormal immune mechanisms. We propose the usefulness of cepharanthine in management of this rare disease.

Autoimmune Pancreatitis Associated with Myelodysplastic Syndrome

A 65-year-old man with myelodysplastic syndrome (MDS) was admitted for progressive jaundice. Diffuse pancreatic swelling and stricture of the main pancreatic duct were observed with elevated serum levels of direct bilirubin, aspartate transaminase, alanine transaminase, alkaline phosphatase, γGTP and amylase, and impaired glucose tolerance. Serum IgG and IgG4 levels were highly elevated, and both the direct antiglobulin test and platelet-associated IgG were positive. He was diagnosed with autoimmune pancreatitis associated with MDS, and biliary drainage followed by immunosuppressive therapy ameliorated the jaundice and laboratory findings. In addition to diffuse pancreatic FDG accumulation, fine incorporations of FDG to the lachrymal and submandibular glands were demonstrated, suggesting the recently proposed IgG4+ multiorgan lymphoproliferative syndrome (MOLPS). The etiology of IgG4+ MOLPS is still unknown; however, autoantibodies to blood cells in this case suggested that the autoimmune mechanism, which is caused by abnormal immune functions in MDS patients, might be involved in the pathogenesis of IgG4+ MOLPS.

Prominent granulomas in bone marrow in disseminated lymphoma with hemophagocytic syndrome.

Dear Editor, An 87-year-old woman was admitted for 5 weeks continued fever, general fatigue, and decreased consciousness level. Neither enlargement of surface lymph nodes (LN) nor skin lesions were present. Laboratory findings revealed WBC 820/μl, hemoglobin 7.8 g/dl, platelet 3.0×10/μl, lactic dehydrogenase 395 IU/l (normal 106–211), C-reactive protein 7.2 mg/dl (normal, <0.3), and serum ferritin 975 ng/ml (normal 2.3–121). The soluble IL-2 receptor (sIL-2R) level was highly elevated (15,280 U/ml; normal, 145–519). Tests for autoantibodies examined or activated viruses including Epstein–Barr virus (EBV) were all negative. Bone marrow (BM) biopsy/aspiration demonstrated hypocellular marrow (nuclear cell count 2.1×10/μl, megakaryocytes 3/μl) without dysplasia or abnormal cells; however, macrophages that phagocytose blood cells were observed (Fig. 1a). Multiple small histiocytic and epithelioid cell granulomas were observed without evidence of acid-fast bacilli or lymphoma, although immunohistochemical analysis was not performed (Fig. 1b, c). Acid-fast staining of the sputum, urine, and blood culture was negative, and the QuantiFERON TB-2G test was also negative, suggesting little participation of tuberculosis in hemophagocytic syndrome (HPS), although there have been several reports of tuberculosis-associated HPS [1, 2]. No apparent masses or LN enlargement was observed in the chest, abdominal, or intracranial areas by computed tomography, Ga scintigraphy, or bone scintigraphy. She was diagnosed as having HPS with unknown etiology. Although 30 mg/day prednisolone accompanied by 100 mg/day cyclosporine was administered, she died after 4 weeks. Autopsy was performed 2 h postmortem with the family’s informed consent. At autopsy, lymphoma cells infiltrated into multiple LNs in pulmonary hilar (Fig. 1d), parabronchial, and para-aortic regions. Lymphoma cells were positive for CD20 (Fig. 1e) and EBV-encoded RNA (EBER) in-situ hybridization, and negative for CD3 (Fig. 1f), CD4, CD8, CD10, CD23, and CD15. Splenomegaly (430 g) was detected, with infiltration of lymphoma cells extending into red pulp (Fig. 1g, h), which also infiltrated into thyroid gland, lung, kidney, liver, and adrenal gland without intravascular growth. BM examination was not diagnostic of lymphoma when the patient was biopsied, but later, at autopsy, obviously, the BM was heavily infiltrated by lymphoma with increased hemophagocytosing macrophages and histiocytic and epithelioid cell granulomas without bacterial or viral growth T. Nagai Department of Internal Medicine, Hyogo Prefectural Tsukaguchi Hospital, Amagasaki, Hyogo, Japan

Disappearing Myelodysplastic Syndrome-Associated Hemolytic Anemia in Leukemic Transformation

Background: Here we report 2 rare cases of acute myeloid leukemia (AML) complicated with hemolytic anemia limited to the myelodysplastic syndrome (MDS) stage, and disappearing in leukemic transformation. Methods/Results: A 66-year-old man with MDS-RAEB-2 was admitted to hospital for severe anemia with increased reticulocyte counts. Hemolytic anemia was suspected, and it was ameliorated by methylprednisolone pulse therapy. Although anemia grew worse when steroids were tapered off, later improvement coincided with an increase in myeloblasts in the peripheral blood, i.e. with leukemic transformation. In another case, a 68-year-old man was admitted to hospital when laboratory findings showed a white blood cell count of 24,800/µl with increased myeloblasts (62.5%), leading to the diagnosis of AML with multilineage dysplasia. Following a decrease in blasts due to anti-cancer drugs, supporting the MDS-RAEB-2 status, severe anemia with increased reticulocytes and positive direct antiglobulin test was diagnosed, suggesting the existence of autoimmune hemolytic anemia, which was then ameliorated by steroid therapy. Conclusions: The simultaneous loss of autoimmunity and leukemic cell expansion observed in our cases may possibly suggest a common underlying mechanism.

Follicular lymphoma with prominent fibrosis complicated by peripheral eosinophilia

Dear Editor, Although eosinophilia is occasionally associated with Hodgkins lymphoma (HL), it only occurs in 5% of non-Hodgkins lymphoma cases, usually in cases of T-cell lymphoma or anaplastic large cell lymphoma. Follicular lymphoma (FL) combined with marked eosinophil expansion is extremely rare, with only two cases reported in the literature [1, 2]. A 47-year-old man first visited the hospital for multiple lymph node (LN) swellings and was diagnosed as FL grades 1/2 by histologic examination (Fig. 1b–e). Lymphoma cells showed positive reactivity for CD10, CD19, CD20, CD23, and κ on flow cytometry. Chromosomal analysis and fluorescence in situ hybridization analysis demonstrated t(14;18)(q32;q21) and IgH–BCL2 fusion signals, respectively. Partial response was obtained by nine courses of combination therapy including cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, mitoxantrone, cladribine, prednisolone (PSL), and rituximab, and since then, he has remained in a stable state for over 2 years without chemotherapy. However, he suffered from itchy eruptions with elevated eosinophils (17.3% of 23,840/μl WBC), which were transiently ameliorated by the administration of 10 mg/day PSL. Biopsies of his skin lesions and bone marrow (BM) revealed no lymphoma cell invasion. BM aspiration showed normocellular marrow with no apparent dysplasia and chromosomal analysis demonstrated normal karyotype. Subsequently, multiple LN swellings with increased volumes were observed with markedly elevated eosinophil counts (7,320/μl), ALP (572 IU/l), LDH (628 IU/l), C-reactive protein (CRP) (13.5 mg/dl), and soluble interleukin (IL)-2 receptor (3,630 U/ml). No obvious causes of the secondary eosinophilia, such as parasitic infection, drugs, vasculitis, or allergic diseases were observed. Although the administration of 30 mg/day of PSL followed by six courses of oral fludarabine and cyclophosphamide ameliorated his eosinophilia (Fig. 1a), a high fever and elevated CRP levels continued with lymphoma progression. Repeated histologic examination revealed that his inguinal LN was occupied by hard fibrous tissue, with a small number of CD20 lymphoma cells in nodular/follicular proliferation without infiltration of eosinophils (Fig. 1f, g). Large cells were proved to be CD68 histiocyte-like cells by immunostaining. The characteristic BCL2–IgH t(14;18)(q32;q21) gene translocation was also detected. He died 3 months later, and autopsy was performed with his familys consent, which revealed lymphoma cell infiltration into multiple LN combined with prominent fibrosis. BM was heavily infiltrated by lymphoma cells and displayed massive fibrosis (Fig. 1h, i). IL-5 specifically promotes the development and differentiation of eosinophils [3], and IL-5 mRNA is expressed in Reed–Sternberg cells of HL cases with eosinophilia [4]. However, IL-5 was not detected, whereas IL-8 level was greatly increased in his serum (228.4 pg/ml; normal <5) when prominent peripheral eosinophilia was observed (August 11, 2008) and then decreased (14.7 pg/ml, April R. Tabata (*) : T. Nagai Department of Internal Medicine, Hyogo Prefectural Tsukaguchi Hospital, 6-8-17 Minamitsukaguchi, Amagasaki, Hyogo 661-0012, Japan e-mail: rtabata@hp.pref.hyogo.jp

Extranodal follicular lymphoma exclusively featured by diffuse pattern originating from multiple vertebral bones

Dear Editor, A 73-year-old woman was admitted due to progressive bilateral paralysis and sensory disturbance of lower extremities. Magnetic resonance imaging (MRI) demonstrated bone masses at C2, C6, and Th8-10 (Fig. 1a) with no masses growing into the spinal canal, and the dural sac was not compressed. Increased uptake to the affected spines of Tc in bone scintigraphy was observed (Fig. 1b). No lesions other than vertebral bones were observed by sonogram, Ga scintigraphy, computed tomography (CT), or MRI. Laboratory findings revealed the almost normal levels except a slightly elevated level of soluble interleukin2 receptor (767U/mL). The histologic examination by fine needle biopsy from Th9 revealed diffuse expansion of small-sized lymphocytes (Fig. 1c,d), and many of them showed positive reactivity for L26. She was diagnosed as having primary malignant lymphoma of the bone (PBL) and treated with radiotherapy to the affected spines, and the subsequent six courses of chemotherapy with rituximab, which induced prompt resolution of the symptoms and MRI findings returned to normal. After 6 months, however, the left parotid gland enlarged progressively (Fig. 1e) with increased uptake of Ga. No other lesions were observed by sonogram, CT, or bone scintigraphy. Histological examination demonstrated the damaged structure of the parotid gland and the diffuse infiltration of the smallto medium-sized lymphocytes (Fig. 1f). By the additional immunohistological examination, the lymphoma cells of the bone and parotid gland were positive for CD10, CD20, and bcl-2 (Fig. 1g–l), weakly positive for bcl-6 (not shown), and negative for CD3, CD5, or CyclinD1, which was compatible with follicular lymphoma (FL). Chromosomal analysis demonstrated abnormal translocation t(14;18)(q32;q21). By fluorescence in situ hybridization analysis, MALT1, which is present in MALT lymphoma, was not detected. She was finally diagnosed as having extranodal FL of vertebral bones followed by salivary gland lymphoma and treated with three courses of rituximab-combined chemotherapy, followed by four courses of weekly administered rituximab, and her condition improved without any evidence of lymphoma relapse. PBL is rare, accounting for <1% of all lymphomas, and the common sites of PBL have been reported to be at the femur, tibia, mandible, and ilium [1]. In our case, the lesions were spread at C2, C6, and Th8-10, with no other lesions. Although the incidence of a single vertebral lymphoma is reported to be 1.7% of all PBLs, multiple primary vertebral lymphoma without involvement to other bones is extremely rare as we can find only one case in the literature [2]. Non-Hodgkins Lymphoma (NHL) of the salivary gland is also uncommon: its incidence is 4%. In our case, the lymphoma cells from both bone and salivary gland showed positive reactivities for CD10, CD20, and bcl-2, which suggested that the lymphoma from both sites were classified into follicular lymphoma [3, 4]. In the literature, most patients with PBL were B-cell tumors with a diffuse mixed cell or diffuse large cell histology [1], and the most common lymphoma involving the salivary gland Ann Hematol (2008) 87:581–583 DOI 10.1007/s00277-007-0433-0

Richter Syndrome With Follicular Colonization of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Cells Mimicking Follicular Lymphoma

Follicular colonization is occasionally observed in marginal zone lymphoma. In rare cases, it has also been associated with mantle cell lymphoma. Chronic lymphocytic leukemia typically involves nodal or extranodal tissues as diffuse proliferation by complete effacement of the normal architecture. The involvement of chronic lymphocytic leukemia may be less frequently limited to the interfollicular areas. Here, we report a case of Richter syndrome of the small intestine that was initially diagnosed as follicular lymphoma of the gastrointestinal tract because of a partial follicular growth pattern in addition to a mainly diffuse proliferation pattern. The follicular pattern mimicking follicular lymphoma was shown to be composed of reactive follicles with follicular colonization of the original chronic lymphocytic leukemia cells. As the prognoses of Richter syndrome and follicular lymphoma of gastrointestinal tract are quite different, clinicians must carefully diagnose these conditions to avoid a misdiagnosis.

Nodal marginal zone B cell lymphoma with prominent follicular colonization with deletion of chromosome 13

Nodal marginal zone B cell lymphoma is a rare type of malignant lymphoma and appears to be heterogeneous. Here we report a 60-year-old woman with stage I splenic type of nodal marginal zone B cell lymphoma with prominent follicular colonization. She was treated only by radiation therapy, and remained free of disease on examination for 4 years. The lymph node cells showed an abnormal chromosome of deletion 13, although neither bone marrow cells nor peripheral blood cells demonstrated the same abnormal chromosome. This type of chromosomal abnormality has not been previously reported and may be related to good prognosis in the present case.

C reactive protein as a predictor of neutrophil recovery in autoimmune neutropenia

Primary autoimmune neutropenia (AIN) is more common in newborns, and usually benign or self-limiting, so most cases require no specific therapy. In adults, however, for little tendency toward spontaneous remission, they require certain treatments and careful managements. Here we report a successful management of primary AIN patient by estimating the granulopoiesis according to CRP levels without administration of G-CSF or increase of prednisolone when peripheral neutrophil counts dropped down. Transient elevation of CRP associated with severe drop down in neutrophil count, and subsequent dramatic neutrophil increase was occasionally observed during the follow up with minimal dose of prednisolone. Coexistence of decreased neutrophil counts and elevated CRP levels was accompanied by increase of serum levels of IL-6 and IL-8. Although this is the report of only one patient, these elevated CRP levels combined with severe drop down and subsequently spontaneous rapid recovery in neutrophil count, were repetitively observed, suggesting the preceding CRP elevation before neutrophil recovery. We propose the important part of CRP as a predictor of granulopoiesis in patients with neutropenia.