Polyclonal Hyperimmunoglobulinemia Research Articles

TAFRO Syndrome: A Syndrome or a Subtype of Multicentric Castleman Disease?

TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis of bone marrow/renal dysfunction, organomegaly) syndrome is a systemic inflammatory disorder of unknown etiology. It has been recognized as a subtype of idiopathic multicentric Castleman disease (iMCD), and the international diagnostic criteria for iMCD-TAFRO require a lymph node histopathology consistent with iMCD. Furthermore, TAFRO syndrome is defined as a heterogeneous clinical entity caused by underlying diseases such as malignancy, autoimmune diseases, or infections. However, the cases that led to the proposal of TAFRO syndrome lacked recognizable lymphadenopathy and were inconsistent with any other diseases, despite vigorous efforts in differential diagnosis. Irrespective of the presence or absence of Castleman disease (CD)-like histology, TAFRO syndrome exhibits homogeneous clinical, laboratory, and prognostic features, setting it apart from iMCD without TAFRO syndrome. Defining iMCD-TAFRO apart from TAFRO syndrome is deemed meaningless and confusing. MCD is a heterogeneous lymphoproliferative disorder consisting of several subtypes with different pathogenesis, clinical manifestations, and histological features. Typical MCD in Japan, characterized by the histology of plasma cell type and marked polyclonal hypergammaglobulinemia, is identical to idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia (IPL). Although IPL is classified into iMCD-NOS (not otherwise specified), it should be recognized as a distinct clinicopathological entity. Furthermore, we propose to separate TAFRO syndrome from the MCD category as a defined disorder.

Idiopathic plasmacytic lymphadenopathy: A conceptual history along with a translation of the original Japanese article published in 1980.

The current consensus on Castleman disease is that it is a group of several distinct lymphoproliferative disorders with different underlying pathogenesis and clinical outcomes. In 1980, Mori et al. proposed the concept of idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia (IPL), a disease of unknown etiology, characterized by severe polyclonal hypergammaglobulinemia and generalized superficial lymphadenopathy. After Frizzera et al.’s landmark report in 1983, the term multicentric Castleman disease (MCD) gradually became established, and for a time, IPL was regarded as identical to MCD. However, with the subsequent recognition of human herpesvirus 8 (HHV8)-related MCD in the 1990s and the contributions by Kojima et al. in the 2000s, in which non-HHV8-related MCD (now called idiopathic MCD) was at least subclassified into IPL and others (non-IPL), it is now clear that the original distinctiveness of IPL is still maintained in MCD, which is a diverse collection of diseases.

Syndrome de TAFRO et gammapathie monoclonale : association inhabituelle !

Castleman's disease is a lymphoproliferative disorder characterized by angiofollicular lymph node hyperplasia. Recently, a new variant of multicentric Castleman's disease has been identified in Japan called TAFRO syndrome. It is characterized by a constellation of symptoms: thrombocytopenia, anasarca, reticulin fibrosis of the bone marrow, renal dysfunction and organomegaly (TAFRO). It is usually associated with polyclonal hyperimmunoglobulinemia. Here, we report the first and unique case of TAFRO syndrome with monoclonal gammapathy.

Clinical Analysis of Anemia in Castleman Disease

This study was to explore the characteristics of anemia in Castleman disease (CD). Clinical data were collected retrospectively to analyze the prevalence and characteristics of CD with anemia were analysed retrospectively, and different types of anemia and their therapeutic effects were evaluated. Anemia was observed in 13/33(39%) newly diagnosed CD patients, most of them was mild and normocytic. Incidence of anemia in multicentric CD (MCD) was higher than that in unicentric CD (UCD) (85% vs 10%, P<0.001). Most of CD patients with anemia presented systematic manifestations; moreover, they had higher levels of erythrocyte sedimentation and inflammatory indices, higher incidence of polyclonal hyperimmunoglobulinemia, and higher positive rate of autoantibodies than those without anemia (P<0.05). Except for 2 cases of autoimmune hemolytic anemia (AIHA) and 1 case of anemia secondary to hypersplenism, the anemia in the other 10 patients exhibited features similar to anemia of chronic disease (ACD), whose hemoglobin levels were negatively correlated with the serum levels of C reactive protein and fibrinogen (r -0.917 and -0.717, respectively, P<0.001). Anemia in UCD was cured by the removal of tumor. Yet, anemia in MCD was improved after systemic treatment with immunotherapy and/or chemotherapy. anemia with an inflammatory and immunologic mechanism presents as a common symptom in MCD, but also can be observed in UCD. In addition to occasional AIHA, anemia associated with CD mainly presents characteristics of ACD. Treatment for anemia in CD is mainly based on the control of primary disease.

慢性腎不全を合併したIdiopathic Plasmacytic Lymphadenopathy with Polyclonal Hyperimmunoglobulinemia(IPL)の1例

慢性腎不全を合併したIdiopathic Plasmacytic Lymphadenopathy with Polyclonal Hyperimmunoglobulinemia(IPL)の1例

皮膚浸潤を伴ったIdiopathic Plasmacytic Lymphadenopathy with Polyclonal Hyperimmunoglobulinemia (IPL)

皮膚浸潤を伴ったIdiopathic Plasmacytic Lymphadenopathy with Polyclonal Hyperimmunoglobulinemia (IPL)

Clinical Implications of Idiopathic Multicentric Castleman Disease Among Japanese: A Report of 28 Cases

To clarify the clinicopathologic findings of idiopathic multicentric Castleman disease among Japanese, 28 cases were studied. Two variants were delineated by the clinicopathologic findings (1) idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia (n = 18) and (2) nonidiopathic plasmacytic lymphadenopathy type (n= 10). Clinicopathologically, idiopathic plasmacytic lymphadenopathy was defined by the prominent polyclonal hyperimmunoglobulinemia, normal germinal centers, and sheet-like infiltration of plasma cells in the interfollicular area of the lymph node. Histologically, the nonidiopathic plasmacytic lymphadenopathy type was characterized by hyaline-vascular germinal centers of the lymph node lesion. In comparison with idiopathic plasmacytic lymphadenopathy, patients with nonidiopathic plasmacytic lymphadenopathy showed infrequent prominent polyclonal hyperimmunoglobulinemia and frequent association with autoimmune disease. However, there was no difference in the overall 5-year survival between the 2 subtypes. Compared with idiopathic multicentric Castleman disease in Western countries, the chronic course of the disease of idiopathic multicentric Castleman disease in Japan appears to be related to negativity for human herpesvirus 8 infection.

Lymphoplasmacytic Infiltrate of Regional Lymph Nodes in Küttner's Tumor (Chronic Sclerosing Sialadenitis): A Report of 3 Cases

Regional lymph nodes of Küttner's tumor from 3 patients showed reactive follicular hyperplasia and prominent interfollicular plasmacytosis. The patients were 71-, 57-, and 73-year-old Japanese men. The polytypic nature of plasma cells was demonstrated by immunohistochemistry. There were numerous IgG-positive plasma cells with scattered IgA-positive or IgM-positive plasma cells. IgG4-positive cells comprised 25% to 40% of IgG-positive plasma cells. Prominent polyclonal hyperimmunoglobulinemia was demonstrated on laboratory test in 2 cases examined. An elevated serum IgG4 level (16%) was also demonstrated in 1 patient. The present 3 cases indicated that regional lymph node of Küttner's tumor may show reactive follicular hyperplasia and prominent interfollicular plasmacytosis and should be differentiated from various benign and malignant lymphoproliferative disorders including systemic rheumatic disease, plasma cell type of Castleman disease, and lymph node involvement of marginal B-cell lymphoma of the mucosa-associated lymphoid tissue type showing prominent plasma cell differentiation.

Bone marrow plasmacytosis in idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia––A report of four cases

We report on bone marrow plasmacytosis in four cases of idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia (IPL). Pathologically, the plasma cells increased in number and accounted for 20–40% of nucleated cells of bone marrow. These plasma cells diffusely infiltrated or formed numerous clusters with 50–200 cells on histological sections. Some binuclear plasma cells and Russell bodies were seen, but all plasma cells showed mature cytomorphology. One case contained two lymphoid follicles with normal germinal centers. Immunoperoxidase studies of light chain determinants for plasma cells and their precursors demonstrated a polyclonal pattern. The immunohistochemical study revealed that there were no human herpes virus-8-positive cells. Bone marrow plasmacytosis of striking proportions may occur in a number of inflammatory conditions, chronic infections, autoimmune diseases, and hypersensitivity states. These reactive plasmacytoses, although sometimes striking, are generally composed of scattered, non-aggregated plasma cells. The four cases described here contained numerous tumor-like aggregations on mature plasma cells. Our four cases should be differentiated from plasma cell myeloma composed of mature plasma cells. However, electrophoresis generally demonstrated a broad-based polyclonal hypergammmaglobulinemia. Moreover, the immunohistochemical study revealed a polytypic nature of the plasma cells. To avoid overdiagnosis and overtreatment, it is important to be aware of the bone marrow findings of IPL.

Idiopathic multicentric Castleman's disease. A clinicopathologic and immunohistochemical study of five cases

Several lymphoproliferative disorders may be interpreted as multicentric Castleman's disease (MCD) clinicopathologically. These include HIV infection, autoimmune-disease-associated lymphadenopathy, idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia, “idiopathic MCD”, POEMS syndrome (polyneuropathy, anasarca, organomegaly, endocrinopathy, M-proteins, and skin lesions), and non-Hodgkin's lymphomas. Among these, idiopathic MCD appears to be relatively rare. We report on the clinicopathologic and immunohistologic findings of five cases of idiopathic MCD and discuss the problems regarding their differential diagnosis. Some of the characteristic clinical findings of POEMS syndrome, including hepatosplenomegaly, skin change, endocrine abnormalities and anasarca, were present in all five cases. However, during the course of disease, minimal diagnostic criteria for POEMS syndrome, i.e., monoclonal plasma cell proliferation and sensory motor neuropathys, were absent in all five cases. The serum interleukin-6 level and the vascular endothelial growth factor level were found to be elevated in two of the cases examined. Various autoantibodies were detected in three cases. However, none of them fulfilled the diagnostic criteria for any of the definite autoimmune-disease. Histologically, three lesions exhibited a mixed type of Castleman's disease, and two exhibited the hyaline-vascular type. The majority of the germinal centers were of the hyaline-vascular or epithelioid germinal type, with a few hyperplastic germinal centers. The interfollicular area was characterized by prominent vascularity. Moderate to large sheets of plasma cells were observed in three mixed type cases. The polytypic nature of B-lymphocytes was demonstrated by immunohistochemistry and polymerase chain reaction. Immunohistochemical study demonstrated that the majority of germinal centers exhibited a tight/concentric pattern of FDC network. Few CD57-positive T-cells were observed in the hyaline-vascular and epithelioid follicles. The lack of CD57-positive T-cells appears to be related to the formation of abnormal germinal centers in the MCD.

Clinical Implication of Florid Reactive Follicular Hyperplasia in Japanese Patients 60 Years or Older: A Study of 46 Cases

Florid reactive follicular hyperplasia (FRFH) of the enlarged lymph node in middle-aged or elderly patients requiring biopsy is a relatively uncommon phenomenon as compared with that in younger age groups. Between 1984 and January 2004, we encountered 46 patients, aged 60 years or older, in whom histology of biopsied lymph node specimens showed inappropriate FRFH for the patient's age. An apparent cause of lymphadenopathy was initially identified in 17 cases (37%): 11 with autoimmune disease and related disorders, 3 with cancer-reactive lymphadenopathy, 2 with Epstein-Barr virus-associated lymph node lesion exhibiting transient autoimmune-disease-like clinical findings, and 1 with atypical mycobacterial infection. Among 29 patients without specific etiology, 16 patients (55%) exhibited histologic findings of progressive transformed germinal center (PTGC). Only 1 of our patients developed malignant lymphoma during the follow-up period. The present study indicates that PTGC is included in the etiology of FRFH in elderly Japanese patients as well as imbalance of the immune system such as autoimmune-disease-associated lymphadenopathy and idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia. By in situ hybridization, Epstein-Barr virus genomes were demonstrated in only 6 (15%) of 39 cases examined.

Minimal change nephrotic syndrome, lymphadenopathy and hyperimmunoglobulinemia after immunization with a pneumococcal vaccine

A 67-year-old female was admitted to our hospital with eruption and cervical lymphadenopathy which occurred one week after pneumococcal vaccination. Polyclonal hyperimmunoglobulinemia (IgG 6,620 mg/dl) and mild plasma cell proliferation (6.4%) in a bone marrow specimen were found, but a lymph node aspiration biopsy showed no specific findings. Normochromic and normocytic anemia with a positive direct Coombs test were also confirmed. Short-term intensive steroid therapy was given, but the systemic eruption and lymphadenopathy continued. About 4 months after vaccination, she suffered from edema in her face and legs and visual disturbance. When massive proteinuria (10.4 g/day) was found, she was admitted to our ward. A renal biopsy specimen showed a minor glomerular abnormality with mild interstitial plasmacytic infiltration. An abdominal CT scan showed hepatosplenomegaly and para-aortic lymphadenopathy. Uveitis was also found by ophthalmoscopy. These abnormalities completely disappeared after intensive steroid therapy including pulse therapy. On the basis of her clinical course and laboratory findings, it was suggested that minimal change nephrotic syndrome might be induced after vaccination, possibly due to hypersensitivity syndrome.

慢性腎炎を合併したIdiopathic Plasmacytic Lymphadenopathy with Polyclonal Hyperimmunoglobulinemia(IPL)の一例

慢性腎炎を合併したIdiopathic Plasmacytic Lymphadenopathy with Polyclonal Hyperimmunoglobulinemia(IPL)の一例

血清中のＩＬ‐６が高値を呈し高度の貧血を併発したＩｄｉｏｐａｔｈｉｃ Ｐｌａｓｍａｃｙｔｉｃ Ｌｙｍｐｈａｄｅｎｏｐａｔｈｙ ｗｉｔｈ Ｐｏｌｙｃｌｏｎａｌ Ｈｙｐｅｒｉｍｍｕｎｏｇｌｏｂｕｌｉｎｅｍｉａ（ＩＰＬ）

A 24-year-old female who was diagnosed as having idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia (IPL) was admitted to our hospital because of general fatigue and fever. Physical examination revealed general lymphadenopathy but no hepatosplenomegaly. Hematological findings were: red cell count, 283×104/μl; hemoglobin 4.9g/dl; hematocrit, 33%; platelet, 72.6×104/μl; and white cell count, 11000/μl. Cervical lymph node rebiopsy revealed folliclar hyperplasia with germinal centers, prominent mature plasma cells proliferation between follicles and sinuses, and the findings were identical to those of IPL. After administration of prednisone, the hemoglobin level increased to 9.0g/dl accompanied by a reduction in lymphadenopathy. However, she did not achieve complete remission.Before administration of prednisolone, Interleukin-6 activities in serum as well as the supernatants of lymph node cell and peripheral blood leukocyte cultures were 2.07, 21.3 and 6.6U/ml, respectively.

A Case of Idipathic Plasmacytic Lymphadenopathy with Polyclonal Hyperimmunoglobulinemia Concurrent with Severe Anemia and Hyperviscosity Syndrome

A Case of Idipathic Plasmacytic Lymphadenopathy with Polyclonal Hyperimmunoglobulinemia Concurrent with Severe Anemia and Hyperviscosity Syndrome

IDIOPATHIC PORTAL HYPERTENSION ASSOCIATED WITH POLYCLONAL HYPERIMMUNOGLOBULINEMIA

We report a case of idiopathic portal hypertension associated with prominent polyclonal hyperimmunoglobulinemia and plasmacytosis in the bone marrow and the spleen. Microscopic examination of the liver showed chronic inflammation in the portal area and abnormal vasculature adjacent to the portal tracts. In the spleen, polyclonal plasma cell proliferation was demonstrated histochemically in addition to the presence of remarkable sinus hyperplasia and periarterial fibrosis. In the present case, a chronic inflammatory state such as connective tissue disease was strongly suspected to exist in the liver, since pancytopenia and hyperimmunoglobulinemia persisted even after splenectomy. It is suggested that the pathogenesis in the present case may have been due to this chronic inflammatory state.

A CASE OF INFLAMMATORY PSEUDOTUMOR OF THE LIVER

A 65-year-old male patient with chief complaints of pyrexia and epigastralgia was treated. Examinations revealed anemia, an increased erythrocyte sedimentation rate, leukocytosis, polyclonal hyperimmunoglobulinemia and reactive hyperplasia of plasma cells in the bone marrow. Abdominal CT visualized a low-density area with an obscure demarcation in the posterior segment of the right hepatic lobe, and angiography showed vascular hyperplasia in the posterior branch of the right hepatic artery. Under a suspicion of liver abscess, exploratory centesis was preformed, but neither purulent discharge nor definite formation of an abscess cavity was found. By needle biopsy, the liver tissue was found to have been replaced by an inflammatory granulation tissue consisting of many plasma cells, lymphocytes and fibroblasts, but no microabscesses were observed. These findings led to the diagnosis of inflammatory pseudotumor of the liver (histopathologically, plasma cell granuloma). As a possible etiology of this disease, it was speculated that some immunological abnormality was involved, for our case presented with polyclonal hyperimmunoglobulinemia and hyperplasia of plasma cells in the bone marrow.

Chronic Myelomonocytic Leukemia According to FAB Classification: Analysis of 35 Cases

Thirty-five patients who fulfilled the FAB diagnosis criteria of chronic myelomonocytic leukemia (CMML), i.e., myelodysplastic features, monocytosis over 10(9)/liter, bone marrow monocyte infiltration, blast cells less than 5% in the peripheral blood and less than 30% in the bone marrow, are analyzed. CMML appears as an entity distinct from myelodysplastic and myeloproliferative disorders. Splenomegaly, anemia, thrombocytopenia, leukocytosis with monocytes and granulocytic cells in all stages of development, increased blood and urine lysozyme levels without renal failure, and polyclonal hyperimmunoglobulinemia are its main clinical and biologic features. With conventional cytotoxic drugs (6-mercaptopurine, hydroxyurea), the prognosis of CMML appears poor (median survival 475 days). None of the clinical hematologic or biologic parameters tested had a significant effect on prognosis. As other chemotherapy trials seemed necessary, we recently administered small doses of cytosine-arabinoside (ARA-C) to six patients over several consecutive days and obtained a complete remission in four. These preliminary results must be confirmed by larger series using the diagnostic criteria proposed by the FAB cooperative group.

Chronic myelomonocytic leukemia according to FAB classification: analysis of 35 cases

Thirty-five patients who fulfilled the FAB diagnosis criteria of chronic myelomonocytic leukemia (CMML), i.e., myelodysplastic features, monocytosis over 10(9)/liter, bone marrow monocyte infiltration, blast cells less than 5% in the peripheral blood and less than 30% in the bone marrow, are analyzed. CMML appears as an entity distinct from myelodysplastic and myeloproliferative disorders. Splenomegaly, anemia, thrombocytopenia, leukocytosis with monocytes and granulocytic cells in all stages of development, increased blood and urine lysozyme levels without renal failure, and polyclonal hyperimmunoglobulinemia are its main clinical and biologic features. With conventional cytotoxic drugs (6-mercaptopurine, hydroxyurea), the prognosis of CMML appears poor (median survival 475 days). None of the clinical hematologic or biologic parameters tested had a significant effect on prognosis. As other chemotherapy trials seemed necessary, we recently administered small doses of cytosine-arabinoside (ARA-C) to six patients over several consecutive days and obtained a complete remission in four. These preliminary results must be confirmed by larger series using the diagnostic criteria proposed by the FAB cooperative group.

多クローン性高免疫グロブリン血症を伴ったB cell Lymphomaの1例

多クローン性高免疫グロブリン血症を伴ったB cell Lymphomaの1例