症例は 73 歳男性。半年間で 10 kg の体重減少と，血液検査で貧血と血小板減少を認められ，当科に紹介，入院となった。頸胸腹部造影CTでは全身のリンパ節腫脹，胸腹水を認めた。鼠径・頸部リンパ節および骨髄生検では有意な所見は認めなかった。入院後に腎機能低下，CRP上昇，発熱を認めた。感染症，自己免疫疾患，悪性腫瘍等を否定し，症候群と診断した。プレドニゾロン内服治療により，臨床症状および血液検査所見は改善した。本症例はiMCD-国際診断基準のTAFROsyndrome, not iMCD-（その内，除外基準に該当する疾患の並存を認めないもの）に当たるが，報告例は稀である。また，iMCD-とiMCD-NOSの特徴が混在していたため，その臨床像について報告する。

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The patient was a Japanese male in his 70s who had previously been treated with an interferon preparation for chronic hepatitis C, but the treatment was ineffective. After edema appeared, computed tomography showed subcutaneous edema, pleural effusion, and ascites, and hepatic edema and ascites were initially suspected because of persistent hepatitis C virus (HCV) infection, thrombocytopenia, and a high FIB-4 index. Noninvasive testing (NIT), which included Mac2 binding protein glycosylation isomer (M2BPGi), ultrasound elastography, and congestion index of the portal vein, ruled out liver cirrhosis and hepatic ascites, and this case was ultimately considered to be

syndrome. The most common cause of ascites is liver cirrhosis, which is often treated by a hepatologist. Thus, it is important to objectively differentiate whether ascites is due to a hepatic cause using NIT. And since there have been no reports of HCV infection complicated by syndrome, this case is rare and valuable.

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Since thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly (

) syndrome was first proposed in 2010, there has been considerable progress in this area, particularly regarding its association with idiopathic multicentric Castleman disease (iMCD). syndrome is a heterogeneous category with a constellation of symptoms that can develop in the setting of infection, rheumatologic disorder, malignancy, and iMCD. Now, iMCD with symptoms is subtyped as iMCD-. However, confusion between syndrome and iMCD- remains. In this article, we discuss the current understanding and future research agenda of syndrome and iMCD- from the perspective of its new validated international definition.

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症候群は体液貯留, 血小板減少, 進行性腎機能障害を呈する全身性炎症性疾患である。症候群に対する免疫抑制療法中に腸骨筋出血をきたして動脈塞栓術を施行した症例を経験した。症例は84歳の男性。呼吸困難を主訴に前医受診。両側胸水貯留, 腎機能障害, 血小板減少, 高度炎症反応上昇がみられた。抗菌薬不応性で, 血小板減少と腎機能障害が増悪し入院17日目に当院に転院した。症候群と診断し免疫抑制療法を開始した。血液透析を導入, 頻回の輸血補充療法を実施した。転院後第20病日に貧血精査の造影CT画像で造影剤の血管外漏出像を伴う右腸骨筋血腫が判明し緊急動脈塞栓術を施行した。その後は原疾患治療継続により腎機能と血小板数は回復し紹介元へ転院した。局所の出血制御と原疾患治療で対応し, 良好な患者予後を得た。症候群では迅速な出血制御が必要な場合も念頭に置きながら精査加療していく必要がある。

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Thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly comprise

syndrome, which was proposed as a distinct clinical entity from iMCD without syndrome (iMCD-NOS) due to its aggressive clinical course, refractoriness to corticosteroids, presence of thrombocytopenia, increased level of alkaline phosphatase, and normal level of gammaglobulin. However, diagnosing syndrome in its early stages is challenging because it is rare and its diagnostic criteria are complicated. We describe a patient with syndrome and adrenal hemorrhage who demonstrated a rapid decline in her clinical condition and did not respond to steroid pulse therapy, resulting in a fatal outcome. In the early stage of her clinical course, she developed unilateral adrenal hemorrhage with mild thrombocytopenia and normal clotting times, suggesting adrenal hemorrhage as a unique manifestation of syndrome. In general, patients with syndrome exhibit a more aggressive clinical course and poorer outcome than those with iMCD-NOS. To ameliorate this poor prognosis, it is important to diagnose the disease early and immediately start powerful immunosuppressive agents such as tocilizumab. Based on this case, adrenal hemorrhage may suggest syndrome, and facilitate the rapid diagnosis of this complicated and rare disease.

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syndrome is a rare systemic inflammatory disease characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly. We encountered a case of calreticulin mutation-positive essential thrombocythemia (ET) with syndrome-like features, followed by a rapid fatal course. The patient had been on anagrelide therapy for approximately three years for management of ET; however, she suddenly stopped going for follow-up and discontinued the medicine for a year. She presented with fever and hypotension, suggestive of septic shock, and was transferred to our hospital. The platelet count at the time of admission to another hospital was 50 × 10⁴ / μL; however, it decreased to 25 × 10⁴ / μL upon transfer to our hospital and further decreased to 5 × 10⁴ / μL on the day of her death. In addition, the patient showed remarkable systemic edema and progression of organomegaly. Her condition suddenly worsened and led to her death on the 7th day of hospitalization. Postmortem, serum and pleural effusion interleukin (IL)-6 and vascular endothelial growth factor (VEGF) levels were significantly increased. Consequently, a diagnosis of syndrome, since she met the diagnostic criteria for clinical findings and had high cytokine concentrations. Dysregulation of cytokine networks has also been reported in ET. Therefore, concurrent ET and syndrome may have further triggered cytokine storms and contributed to the aggravation of the disease on development of syndrome. To the best of our knowledge, this is the first report of complications seen in a patient with syndrome due to ET.

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80歳男性。主訴は胸水貯留。1年半前から労作時息切れ, 下腿浮腫を認め, 完全房室ブロックに伴う心不全と当院循環器内科でペースメーカー植込み等を施行された。しかし胸水貯留を繰り返すため当科に紹介入院精査となった。全身性浮腫, CT上は胸腹水貯留と縦隔リンパ節の腫大, 採血では汎血球減少とCRPの上昇を認めた。

症候群等を疑い精査を開始したが, 呼吸状態が悪化したため, 第6病日にICU入室, 人工呼吸開始となった。確定診断前ではあったがステロイドパルスを施行したところ, 胸水減少および呼吸状態の改善がみられた。第20病日に人工呼吸器を離脱し, 第24病日ICU退室となった。本症例は難治性胸水とリンパ節腫大, 血球減少より症候群を疑い, ステロイドによる治療を開始して改善が得られた。難治性胸腹水にリンパ節腫大, 血球減少を認めた場合は上記疾患も念頭に置き, 診断された際にはステロイドによる治療を検討すべきと考えた。

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The clinical manifestations of idiopathic multicentric Castleman disease (iMCD) are thought to be caused by an excess of inflammatory cytokines; however, the mechanism is yet to be known. In addition to IL-6, inflammatory cytokines, such as IL-1β and TNF-α, are noted to be elevated in iMCD, which are common in autoinflammatory diseases. The first-line treatment for iMCD is an IL-6 inhibitor. Furthermore, increases in inflammatory cytokines such as serum IL-10 and IL-23, chemokines such as CXCL13 and CXCL-10 (especially in iMCD-

), and VEGF-A have been observed, and their relationship to pathogenesis has attracted the attention of researchers. The PI3K/Akt/mTOR pathway, JAK/STAT3 pathway, and type I IFN as drivers have recently been identified as important signals and are expected to be therapeutic targets in cases where IL-6 inhibitors are ineffective.

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Castleman disease is a polyclonal lymphoproliferative disease which is clinically classified into unicentric (UCD) and multicentric (MCD).

syndrome is a relatively new concept that partly overlaps with MCD. Due to their rarity, their incidence remains unknown. This study investigated the incidence and prevalence of UCD, MCD, and syndrome in Japan using a fixed-point observation method based on their incidence in Ishikawa prefecture. The annual incidences of MCD, UCD, and syndrome in Japan were 309-731, 71-542, and 110-502, respectively, yielding annual incidence rates per million individuals of 2.4-5.8, 0.6-4.3, and 0.9-4.9, respectively, and nationwide prevalence of 4,180-14,900, 1,350-10,300, and 860-7,240, respectively. In conclusion, MCD, UCD and syndrome may not be as rare as previously estimated in Japan.

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Castleman disease consists of several lymphoproliferative subtypes that share some histological features in the lymph nodes. On the other hand, numerous clinical findings and etiologies make the disease challenging to understand. The origin of the disease is the hyaline vascular-type unicentric Castleman disease (UCD), first reported by Benjamin Castleman et al. in 1954. Although UCD is characterized by localized lesions and lack of symptoms, multicentric Castleman disease (MCD) with multiple lesions and systemic symptoms was reported by Frizzera in 1983. MCD is further divided according to KSHV/HHV8 infection status. In KSHV/HHV8-related MCD, viral infection signals lead to excessive cytokine production, and cause clinical and pathologic abnormalities. Some cases of plasma cell-type KSHV/HHV8-negative MCD can be found in association with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-proteins, and skin changes), which is a paraneoplastic syndrome. The others are idiopathic MCD, which are currently considered a heterogeneous group of diseases with overlapping pathological and clinical features. In this article, we summarize the historical evolution of Castleman disease to help understand the disease concept. We also review the latest ideas and definitions of the subtypes within the MCD spectrum and summarize the histopathological findings.

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Idiopathic multicentric Castleman disease (iMCD) is a systemic disorder characterized by systemic inflammation and organ dysfunction associated with an increase in pro-inflammatory cytokines. Some patients with iMCD are positive for autoantibodies, although their significance and relationship with specific associated autoimmune diseases are unclear. This study retrospectively analyzed the clinicopathological features of iMCD patients focusing on autoantibodies. Among 63 iMCD patients in our database, 19 were positive for at least one autoantibody. Among the 19, we identified five with plasma cell type (PC)-iMCD lymph node histopathology and positive anti-phospholipid antibodies. These patients were likely to have thrombocytopenia, anasarca, fever, reticulin fibrosis or renal insufficiency, organomegaly (

) symptoms, and thrombotic events. The present study suggests that patients with undiagnosed or atypical autoimmune diseases, including anti-phospholipid syndrome (APS), were treated for iMCD. APS may present with thrombocytopenia or even multi-organ failure, which overlap with clinical presentations of iMCD. Due to differences in the treatment regimen and follow-up, recognition of the undiagnosed autoimmune disease process in those suspected of iMCD is essential. Our study highlights the importance of complete exclusion of differential diagnoses in patients with iMCD in their diagnostic workup.

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   syndrome is a newly defined disease entity which is characterized by thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly. A histological pattern of multiple lymphadenopathy of atypical Castleman's disease (CD) is also an important characteristic. A 48-year-old man was referred to our hospital with fever, asthenia, bilateral pleural effusion, ascites, generalized edema, dyspnea, hypoalbuminemia, severe thrombocytopenia, anemia, renal failure and proteinuria, whereas bacterial culture and serological and PCR tests for various viruses were all negative. A CT scan showed multiple lymphadenopathy and tissue sampling of inguinal lymph nodes showed a compatible histology with plasma cell type CD. A diagnosis of syndrome was made. Ten days after hospitalization, sudden cardiac insufficiency and anuria developed. Despite glucocorticoid pulse therapy, tocilizumab and plasmapheresis, clinical and laboratory features did not improve. On the 34^th hospital day, we started rituximab. His general condition started to improve in several days, and by one month later anasarca had improved drastically. Thrombocytopenia and renal function gradually improved and finally normalized. Cardiac motion also improved. This is the first report of a syndrome patient with cardiomyopathy, who was successfully treated with rituximab.

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症例は43歳の男性。2週間前からの腹部膨満感を主訴に受診。発熱，CRP高値，血小板減少，胸腹水，多発リンパ節腫脹を認め入院。腋窩リンパ節生検ではCastleman病の所見だったが，他の臨床的特徴から第10病日に

症候群と診断しステロイド，トシリズマブで治療を開始。しかし腹水が減少せず腹部膨満の苦痛が強い上，腎前性急性腎不全となり，連日のアルブミン製剤使用でも循環管理できず，第11病日より腹水濾過濃縮再静注法（CART），第19病日よりHDFを開始。週2回HDFと週1回腹水濾過還元血液濾過透析（AFR-HDF）により腹水コントロールが可能となり，アルブミン製剤の使用量も減少。種々の免疫抑制療法により徐々に寛解傾向となり第75病日にHDF離脱，その後CARTも不要となり第152病日に退院。症候群の治療法はまだ確立されていない。難治性腹水と急性腎不全を合併する場合に，AFR-HDFは全身管理の手段として有効な選択肢と考えられる。

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Recently, a unique clinicopathologic variant of multicentric Castleman's disease (MCD) has been identified in Japan. This disease is characterized by a constellation of symptoms, as listed in the title, and multiple lymphadenopathy of mild degree with a pathologic diagnosis of atypical CD, often posing diagnostic and therapeutic problems for pathologists and hematologists, respectively. These findings suggest that this disease represents a novel clinical entity belonging to systemic inflammatory disorders with a background of immunological abnormality beyond the ordinal spectrum of MCD. To define this disorder more clearly, Japanese participants presented clinicopathologic data at the Fukushima and Nagoya meetings. Many of the patients presented by the participants were significantly accompanied by a combination of thrombocytopenia, ascites (anasarca), pleural effusions, microcytic anemia, fever, myelofibrosis, renal dysfunction, and organomegaly (). Multiple lymphadenopathies were generally of mild degree, less than 1.5 cm in diameter, and consistently featured the histopathology of mixed- or less hyaline vascular-type CD. Autoantibodies were often detected. However, this disease did not fulfill the diagnostic criteria for well-known autoimmune diseases including systemic lupus erythematosus. Castleman-Kojima disease and syndrome (the favored clinical term) were proposed for this disease. The patients were sensitive to steroid and anti-interleukin-6 receptor antibody (tocilizumab), but some exhibited a deteriorated clinical course despite the treatment. The participants proposed a future nationwide survey and a Japanese consortium to facilitate further clinical and therapeutic studies of this novel disease. [J Clin Exp Hematop 53(1): 57-61, 2013]

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  症例は25歳女性．2013年6月前医で原発性シェーグレン症候群と診断．2014年7月発熱，著明な炎症反応，全身リンパ節腫脹，肝脾腫を認め前医に入院．抗生剤（ceftriaxone，meropenem）を投与，ステロイドを増量（PSL 50mg）するも無効で，急速に進行する全身浮腫を認め当院へ転院．リンパ節生検では好中球浸潤を認め，骨髄穿刺では巨核球増加と線維化を認めた．minomycinを併用したところ，発熱・全身浮腫・炎症反応は徐々に改善したが，貧血・血小板減少を認めていた．感染症を疑いステロイドを減量したところ，再び発熱，浮腫・胸腹水の出現，血小板減少・貧血の増悪を認めた．ステロイドパルス，ステロイド再増量を行うも治療抵抗性で，cyclosporin（CyA）を併用し軽快した．典型的なリンパ節の病理像を認めなかったが，本症例の臨床像は

症候群と酷似していた．症候群は，Castleman病の一亜型と考えられているが，感染，リウマチ性疾患，悪性腫瘍などによる高サイトカイン血症により二次的に生じ得るとされている．本症例では原発性シェーグレン症候群を背景に発症し，化膿性リンパ節炎様のリンパ節病理像を認めた点が興味深いと考え報告する

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【背景】

症候群はmulticentric Castleman's disease（MCD）の亜型とされ，血小板減少症，腔水症，骨髄線維症等を特徴とした稀な炎症性疾患である．MCD同様Interleukin（IL）-6がkey cytokineとされたが，血小板減少等はIL-6作用と矛盾し，Tocilizumab（TCZ）の奏効率はMCDに比して低い．既報でCyclosporineの有用性が示唆され，我々は心筋障害合併例を含む2症例に初めてTacrolimus（TAC）で治療を行った．【症例1】68歳女性．発熱，血小板減少，胸腹水，骨髄線維症とリンパ節生検で症候群と診断した．Glucocorticoids（GC）単剤では症状改善乏しく，TCZを開始したが効果なく，膿胸に伴う敗血症を来した．TACへ変更したところ速やかに寛解に至った．【症例2】17歳男性．発熱，血小板減少，胸腹水の精査中，急性に瀰漫性心筋障害を伴う重症心不全を来した．症候群に伴う心筋障害と診断し，GCとTACで治療開始したところ心筋障害は速やかに可逆的に改善し寛解に至った．【考察】Literature reviewから，症候群でのTCZの奏効率は50％以下で，GCとTCZの併用療法は感染症合併率が高かった．症候群とIL-2，IFN-γ induced protein 10（IP-10）等のTh1 cytokinesの関係が示唆され，心筋障害への関与も想定されることから，Th1 cytokinesを抑制するTACは有望な治療薬と考えられる．本症例はTACが心筋障害合併例を含む症候群に有効かつ安全に使用できることを示す初めての報告である．

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Recently, atypical Castleman's disease (CD) was reported in Japan. This disease is considered as syndrome or non-idiopathic plasmacytic lymphadenopathy (IPL), a constellation of clinical symptoms, namely, thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly without hyper-γ-globulinemia. Histopathologically, this disease is similar to hyaline vascular (HV)-type CD. Here, we present a 43-year-old Japanese woman meeting the clinical criteria of syndrome who was successfully treated with combined corticosteroid therapy. She showed a rapidly progressive course of thrombocytopenia, systemic lymphadenopathy, fever, anasarca, and increase in acute inflammatory proteins without hyper-γ-globulinemia. Lymph node biopsy was performed and revealed HV-type CD without human herpes virus 8 infection, which was clinicopathologically compatible with non-IPL. The association of these atypical features with well-known multicentric Castleman's disease (MCD), namely, HV-type histology with systemic lymphadenopathy, marked thrombocytopenia even with a high level of interleukin-6, and increased acute inflammatory proteins without hyper-γ-globulinemia, suggests that syndrome as presented in our case is a novel entity, which may have been diagnosed as MCD in the past. To define this novel entity more clearly and to demonstrate its etiology, further nationwide surveys of this syndrome and MCD are needed. [J Clin Exp Hematopathol 53(1) : 87-93, 2013]

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