Development of primary central nervous system post-transplant lymphoproliferative disorder immediately after cytomegalovirus viremia in an MDS patient who received cord blood transplantation

　Epstein–Barr virus (EBV) plays a central role in the pathogenesis of posttransplant lymphoproliferative disorder (PTLD), and EBV reactivation after allogenic hematopoietic stem cell transplantation (allo-HSCT) is highly correlated with cytomegalovirus (CMV) reactivation, which might be a risk factor for PTLD. We encountered a myelodysplastic syndrome patient with PTLD in the central nervous system who experienced sequential CMV and EBV reactivation immediately after allo-HSCT. Previous studies have suggested relationships between CMV and EBV reactivation and between CMV reactivation and PTLD. Our case suggests the importance of CMV monitoring in patients after allo-HSCT to preventPTLD

Application of modified shrinking field radiation in RT-DeVIC chemoradiotherapy for treating localized extranodal natural killer/T-cell lymphoma

　Concurrent chemoradiotherapy (CRT) is the recommended treatment for localized extranodal natural killer/T-cell lymphoma, nasal type (ENKL). In 2009, the Japan Clinical Oncology Group first documented the safety and efficacy of a regimen involving radiotherapy (RT) plus dexamethasone, etoposide, ifosfamide, and carboplatin (DeVIC) in their phase I/II trials (JCOG0211 study). The application of this regimen has drastically improved outcomes of patients with localized ENKL. In 2013, the current guidelines were made to the cost in JCOG0211 study.　We retrospectively investigated the outcomes of three patients who received CRT for stage localized ENKL at the Kawasaki Medical School Hospital between August 2007 and March 2011. Our CRT protocol differed from that used in the JCOG0211 study as we used a different shrinking field RT method. A recent report on shrinking or extended-field RT raised questions regarding which fields are appropriate. Thus, we compared our clinical results with those of the JCOG0211 study and analyzed the effect of the differences in field size on clinical results. The median follow-up of the three patients in the present study was 9 months (range, 5-106 months), two and one of whom achieved complete and partial responses, respectively. Regarding adverse events, no severe acute side effects (e.g., mucositis) higher than Grade 4 were observed.　We reviewed cases and the JCOG0211 study which we experienced in the past about fields of the RT. The present study described our experiences with three patients receiving shrinking field RT

胸水細胞診で形質細胞腫が疑われた血管免疫芽球性Ｔ細胞リンパ腫

血管免疫芽球性Ｔ細胞リンパ腫（angioimmunoblastic T-cell lymphoma: AITL）は新WHO分類において末梢Ｔ細胞 / NK 細胞腫瘍に分類されているＴ細胞性腫瘍である．その臨床像は，全身リンパ節腫大，肝脾腫，発熱，多クローン性高γ グロブリン血症など多様な症状を呈することが知られている．今回，我々は胸水細胞診で形質細胞腫が疑われたAITL を経験したので報告する．症例は80歳代の女性．近医にて気管支喘息治療中に，喘息症状が悪化し，全身の皮疹が出現．両側胸水貯留，CRP 高値が出現したため，精査治療目的で当院紹介となった．血液検査で貧血を認め，末梢血に形質細胞様の異型リンパ球を10％認めた．胸水には大小不同のCD138陽性形質細胞を多数認め細胞診で形質細胞腫が疑われたが，胸水セルブロックではκ・λ の軽鎖制限を認めなかった．骨髄検査では，形質細胞の増加を認めず赤芽球癆の状態であった．皮下腫瘤を生検した結果，AITL と診断した．AITL は，腫瘍細胞が直接的・間接的にサイトカインを産生し，それに起因した多彩な臨床像を呈する．そのため，AITL は反応性に形質細胞の増加を伴うことが多く，本症例は，反応性に胸水中に形質細胞の増加を伴ったと考えられた．また，AITL は赤芽球癆を合併することも報告されている．AITL では，反応性の形質細胞増多を伴う胸水貯留や赤芽球癆をきたす場合があることに注意すべきである．Angioimmunoblastic T cell lymphoma (AITL) is a T cell-related tumor that is classified as a peripheral T cell/natural killer cell tumor according to the new World Health Organization classification. AITL shows various clinical features owing to the cytokines produced directly or indirectly by tumor cells and includes a variety of symptoms, such as general lymphadenopathy, hepatosplenomegaly, fever, and polyclonal hypergammaglobulinemia. AITL is often accompanied by reactive plasmacytosis, and it has been reported that AITL can be complicated by pure red cell aplasia. Here, we report an 80-year-old woman with AITL who was suspected to have a plasma cell tumor by cytological diagnosis of hydrothorax. The patient presented with exacerbated asthmatic symptoms as well as exanthema over her entire body. Moreover, during treatment for bronchial asthma at a local doctor’s clinic, hydrothorax in both lungs and high C-reactive protein levels were observed. She was referred to our hospital for detailed examination and treatment. Blood test results revealed anemia as well as a high proportion of plasma cell-like atypical lymphocytes in the peripheral blood. Specimens of the hydrothorax also contained CD138-positive plasma cells of varying sizes; however, there was no evidence of deviation in light chain limitation. We did not notice elevated plasma cell counts, and the patient was considered to have pure red cell aplasia based on the results of the marrow examination. However, we noted a subcutaneous mass under her shoulder blade. An excisional biopsy was performed, and she was diagnosed with AITL. The patient was considered to have hydrothorax with plasmacytosis as a reaction to AITL. As seen in our case, AITL may cause pleural effusions along with reactive plasmacytosis and pure red cell aplasia

Red-cell aplasia due to persistent human parvovirus B19 infection three years after umbilical cord blood transplantation-a case study

　造血幹細胞移植後に生じる貧血は，骨髄の造血能低下やウイルス感染症等の様々な背景が原因となることがあり，診断が困難であることが多い．ヒトパルボウイルス B19（human parvovirus B19：PVB19）は伝染性紅斑の原因ウイルスであり，遺伝性球状赤血球症等の赤血球寿命が短縮している溶血性貧血患者では，急性赤芽球癆を呈することが知られている．PVB19は移植患者を含む免疫不全状態の患者で慢性貧血を引き起こすことがあり，腎移植患者などでの報告例は多く存在するが，臍帯血移植後における PVB19感染による後天性赤芽球癆の症例の報告はほとんどない．今回我々は，臍帯血移植が成功したのち３年を経て発症した PVB19が４か月以上持続感染している症例を経験したので報告する．　Onset of anemia after hematopoietic stem cell transplantation can be caused by various background factors such as reduced hematopoiesis of the bone marrow and viral infection. Therefore, diagnosis is often difficult. Human parvovirus B19 (PVB19) due to acquired pure red-cell aplasia is the causative virus of erythema infectiosum, and it is well known that patients with hemolytic anemia with a short erythrocyte life span such as in the case of hereditary spherocytosis present with acute red-cell aplasia. PVB19 can cause chronic anemia in immunocompromised patients, including transplantation patients, and while there are many reported cases in kidney transplant patients, etc., there are few reported cases of cord blood transplantation. Here, we report a case of onset of PVB19 that occurred three years after successful umbilical cord blood transplantation and caused persistent infection for over a period of four months

臍帯血移植後発症した early lesion of PTLD の剖検例

移植後リンパ増殖性疾患（post-transplant lymphoproliferative disorders, PTLD）は，同種造血幹細胞移植後の生命を脅かす予後不良な合併症の一つである．臨床症状は非特異的であるが，PTLD を疑った場合はPCR 法による血中EB（Epstein-Barr）ウイルス-DNA 量を測定し，高値を示した場合はPTLD と判断する必要がある．今回，造血幹細胞移植後に高EB ウイルス血症を認め，急激な病状の悪化により死亡した症例を経験したため剖検所見を含め報告する．症例は，40歳代男性でフィラデルフィア染色体陽性急性リンパ性白血病を発症し，治療にて寛解を得た後に臍帯血移植を施行した．移植後280日に高熱が出現し，胸部CT 検査から細菌性肺炎と診断し入院．抗菌薬治療を開始するも効果不良であり，呼吸状態の悪化と，意識障害が出現した．血液，肺胞洗浄液と髄液から，EB ウイルス-DNA 異常高値が検出された．PTLD と判断したが，急激に呼吸状態が悪化し死亡した．剖検では，肺胞内出血を認め，急激に悪化した原因と考えられた．そして，肺門部リンパ節や肺にはEBER（EBV-encoded small RNA）陽性細胞を多数認め，一部では大型多核細胞も散見され，early lesion of PTLD と判断された．Early lesion of PTLD であっても，本症例のように肺病変を認めた場合，出血による呼吸状態の悪化から急激な経過をたどることがあり，早期の対応が必要と考えられた．Post-transplant lymphoproliferative disorder (PTLD), a life-threatening condition with poor prognosis, can arise after allogeneic hematopoietic stem cell transplantation. The clinical symptoms are non-specific, but if PTLD is suspected, the blood levels of Epstein-Barr (EB) virus DNA are measured using PCR. Here, we report our experience with a patient who showed high levels of EB virus DNA in the blood and a rapidly worsening condition resulting in death, after undergoing hematopoietic stem cell transplantation. The patient was male and in his 40s; he had developed Philadelphia chromosome-positive acute lymphoid leukemia and achieved remission with treatment, and he later underwent umbilical cord blood transplantation. A high fever appeared 280 days after transplantation, and he was hospitalized and diagnosed with bacterial pneumonia following a thoracic CT examination. He was initiated on antimicrobial therapy, but responded poorly, exhibiting a worsening respiratory condition and disturbance of consciousness. Abnormally high EB virus DNA levels were detected in his blood, bronchoalveolar lavage fluid, and cerebrospinal fluid. He was diagnosed with PTLD, but his respiratory condition deteriorated rapidly and he died. The autopsy revealed alveolar hemorrhage, which was thought to be the cause of the rapid deterioration. A large number of EBER (EBV-encoded small RNA)- positive cells were also found in hilar lymph nodes and lungs, which were deemed to be early lesions of PTLD. Therefore, timely action is crucial if lesions are presents as even early PTLD lesions can progress rapidly owing to bleeding that can result in the deterioration of the respiratory condition

クリプトコッカス髄膜炎を発症したCD4リンパ球減少症の２例

　クリプトコッカス感染症はCryptococcus neoformans による真菌感染症であり，免疫不全患者に発症しやすい．今回，我々はCD4リンパ球減少を認め，クリプトコッカス髄膜炎を発症した２例を経験したので報告する．症例１は，40歳代男性で不明熱のため受診した．血液検査でリンパ球930/μL，髄膜刺激症状はなかったが，髄液検査にてクリプトコッカス菌体が検出され，血液培養からも検出された．CD4 72.5/μL と低値であり，HIV 抗体陽性であった．クリプトコッカス髄膜炎を発症したAIDS 患者と診断した．症例２は，20歳代女性で不明熱のため受診した．血液検査でリンパ球510/μL，髄膜刺激症状はなかったが，髄液検査にてクリプトコッカス菌体が検出され，血液培養からも検出された．CD4 19.4/μL と低値であったが，HIV 抗体陰性で原発性免疫不全症や他の免疫不全となる原因は認められなかった．Idiopathic CD4 lymphocytopenia（ICL）に発症したクリプトコッカス髄膜炎と診断した．AIDS とICL がそれぞれ原因となったクリプトコッカス髄膜炎であった．前者での本症併発は2.4 %，後者での併発は19.7 % と報告されている．HIV非感染のクリプトコッカス髄膜炎をみた際にはICL によるCD4リンパ球減少症を考える必要がある．死に至ることもまれではないクリプトコッカス髄膜炎であるが，治療が奏効し１年以上経過しているため報告する．　Cryptococcal infections are fungal infections caused by Cryptococcus neoformans. This infection develops more commonly in immunocompromised patients. We report two cases of cryptococcal meningitis that developed as a result of CD4 lymphocytopenia. Case 1 was a man in his 40s who presented with a fever of unknown origin. A blood test revealed a lymphocyte count of 930/μL, with no meningeal irritation; however, examination of his cerebrospinal fluid detected cryptococcal bodies, which was also confirmed by blood culture. In addition, the patient had a low CD4 count of 72.5/μL, and was HIV antibodypositive. We thus diagnosed him as an AIDS patient who developed cryptococcal meningitis. Case 2 was a woman in her 20s who also presented with a fever of unknown origin. A blood test revealed a lymphocyte count of 510/μL, with no meningeal irritation; however, examination of her cerebrospinal fluid detected cryptococcal bodies, which was confirmed by blood culture. Despite the patient having a low CD4 count of 19.4/μL, she was HIV antibody-negative, and there was no evidence of primary immunodeficiency or any other causes of immune deficiency. Accordingly, we diagnosed this patient as cryptococcal meningitis that developed as a result of idiopathic CD4 lymphocytopenia (ICL). In the above cases, cryptococcal meningitis developed as a result of AIDS and ICL, respectively. The incidence rates of this complication are reported as 2.4% for the former and 19.7% for the latter. When cryptococcal meningitis without HIV infection is observed, it is necessary to consider the possibility of CD4 lymphocytopenia due to ICL. Although cryptococcal meningitis can be fatal, treatment was successful in both cases, and more than one year has elapsed since their initial presentation

リツキシマブ併用ベンダムスチン療法が奏効した腸管monomorphic PTLD

　移植後リンパ増殖性疾患（PTLD）は，造血幹細胞移植後に免疫抑制剤を使用した結果として，Ｔ細胞機能が低下して生じる異常なリンパ球，または形質細胞の増殖で，移植領域において最も致死的で注意を要する合併症の一つである．PTLD は４つのカテゴリーに分類され，その中のmonomorphic PTLD は、悪性リンパ腫の形態を呈する．Monomorphic PTLD の治療には，免疫抑制剤減量，リツキシマブ（Ｒ）単独療法やR-CHOP 療法があるが，予後は不良である．今回，難治性PTLD に対してリツキシマブ併用ベンダムスチン療法が奏効し寛解をえることができた症例を経験したので報告する．症例は50歳代男性で、骨髄異形成症候群に対して臍帯血移植を施行し，GVHD 予防にタクロリムスを使用した．移植後，消化管GVHD を発症し，プレドニゾロンで治療中，monomorphic PTLD（びまん性大細胞型Ｂ細胞リンパ腫）を発症した．免疫抑制剤中止後，リツキシマブ（Ｒ）単独療法，R-CHOP like 療法を施行したが効果不良であった．リツキシマブ併用ベンダムスチン療法に変更し４コース施行後，消化管内視鏡検査で病変は消失し，CT 検査で完全奏効を確認した．治療終了し約１年経過しているが，現在も症状増悪なく経過できており，難治性monomorphic PTLD に対してリツキシマブ併用ベンダムスチン療法が有効であった．Post-transplantation lymphoproliferative disorder (PTLD) occurs as a result of the use of immunosuppressants following hematopoietic stem cell transplantation, which causes the emergence of abnormal lymphocytes owing to the decline in T-cell function and the proliferation of plasma cells. It is thus one of the most fatal complications and the biggest concern for transplantation cases. PTLD is classified into 4 categories, and monomorphic PTLD takes the form of a malignant lymphoma. Immunosuppressant dose reduction, rituximab (R) monotherapy, and R-CHOP therapy are used to treat monomorphic PTLD, but the prognosis is poor for these forms of treatment. This report describes the experience of a patient with refractory PTLD who went into remission after responding to combination therapy with rituximab and bendamustine. A 50-year-old man underwent cord blood transplantation because of a myelodysplastic syndrome. Tacrolimus was used for GVHD prevention. After transplantation, symptoms of GVHD of the gastrointestinal tract developed, and during treatment using prednisolone, symptoms of monomorphic PTLD (diffuse large B-cell lymphoma) emerged. Once immunosuppressant use was discontinued, the patient underwent R monotherapy and R-CHOPlike treatment, but the response was poor. The treatment was then changed to combination therapy with rituximab and bendamustine; after 4 courses of treatment, gastrointestinal endoscopy revealed that the pathological abnormality had disappeared, and a complete response was confirmed. One year has passed since the completion of treatment, and at present, the patient’s symptoms have not worsened, suggesting that combination therapy with rituximab and bendamustine is effective for treating monomorphic PTLD

形態学的に骨髄腫細胞との鑑別に苦慮した plasmacytoid な形態を示した膀胱癌の多発骨転移の１例

　尿路上皮癌には，腫瘍細胞が形質細胞に酷似した形態を呈することがある．今回，形態学的に骨髄腫細胞との鑑別に苦慮したplasmacytoid な形態を示した膀胱癌の骨髄転移の一例を経験したので報告する．　症例は80歳代男性で，20XX 年10月に蛋白尿と腎機能障害が出現し，精査にて多発性骨髄腫（IgG-λ），ISS Ⅱ期と診断され，BD 療法（bortezomib+dexamethasone）を開始した．効果は良好で，３コース施行後にはVGPR（very good partial response）に到達した．20XX ＋１年２月間歇的に認めていた血尿の精査を行い，細胞診や膀胱鏡検査から膀胱癌の併発を確認した．骨髄腫治療は中断し，膀胱癌治療を優先した．PET/CT 検査ではリンパ節やその他臓器への転移は認めず，６月に膀胱全摘術が施行された．術後は経過良好であったため，全身状態の回復を待ち，骨髄腫治療を再開する予定であった．しかし，９月末頃から腰痛が出現し，10月には腰痛の増強を認めたため再度PET/CT 検査を施行したところ，多発する骨髄病変を認めた．骨髄腫の増悪を疑い骨髄検査を施行した．骨髄穿刺塗沫標本では，形質細胞様の異形細胞を多数認め，骨髄腫の増悪を推測させる所見であった．しかし同時に施行された骨髄腫関連検査では，IgG やその他の免疫グロブリンは正常であり，蛋白分画や免疫固定法でもM 蛋白は検出されなかった．骨髄生検の病理組織学的検査の結果，形質細胞様の異形細胞は尿路上皮系の腫瘍細胞であり，膀胱癌の骨転移と診断された．PET/CT 検査での多発骨髄病変は，多発性骨髄腫の増悪ではなく，膀胱癌の多発骨転移であった．　膀胱全摘後の再発は，遠隔転移が20～50% と遠隔転移が多く，遠隔転移部位として骨，リンパ節，肺，肝の順に多いと報告されている．そのため，骨髄塗抹標本検鏡の際，遭遇する可能性があり，骨髄腫細胞と見誤らないためには，免疫染色を含めた組織学的な検討，血清・尿の蛋白解析が必須と考えられた．　Urothelial cancer cells may appear similar to plasma cells. We present a case of plasmacytoid bladder cancer with bone marrow metastasis and difficult morphological differentiation from myeloma. A male in his 80s presented with proteinuria and renal dysfunction in October 20XX. Detailed examination led to a diagnosis of International Staging System Stage II multiple myeloma (IgG-λ), and BD (bortezomib + dexamethasone) therapy was started. Three courses of treatment resulted in a very good partial response. Intermittent hematuria was observed in February 20XX+1, and cytodiagnosis and cystoscopy confirmed bladder cancer. Myeloma treatment was discontinued, and treatment of bladder cancer was prioritized. There was no metastasis to lymph nodes or other organs on positron emission tomography-computed tomography (PET/CT) and cystectomy was performed in June. The postoperative course was good, and myeloma treatment was to resume once the patient had improved. However, in late September, he developed lower back pain that intensified in October. Repeat PET/ CT confirmed multiple bone marrow lesions. Exacerbation of myeloma was suspected. Bone marrow aspiration confirmed multiple plasma cell-like atypical cells, indicating exacerbation of myeloma. However, other myeloma-related tests performed at the same time, including IgG and immunoglobulins, were normal, and M protein was not detected on protein fractionation or immunofixation. Histopathological examination of a bone marrow biopsy showed that plasma cell-like atypical cells were urothelial tumor cells, and bone metastasis from bladder cancer was diagnosed. Multiple bone marrow lesions found on PET/CT were not an exacerbation of multiple myeloma but instead were multiple bone metastases from bladder cancer.　Recurrence following cystectomy has a high prevalence of distant metastasis (20 to 50%), and distant metastasis sites include bones, lymph nodes, lungs, and liver in the order of prevalence. Therefore, bone marrow aspiration and histological examination with immunostaining, in addition to serum and urine protein analysis are essential to prevent confusion with myeloma cells