Pyothorax-associated Lymphoma Research Articles

EBV-positive pyothorax-associated lymphoma expresses CXCL9 and CXCL10 chemokines that attract cytotoxic lymphocytes via CXCR3.

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) develops in the setting of long-standing inflammation. This type of lymphoma may have specific expression profiles of chemokines involved in the pathogenesis of DLBCL-CI. EBV-positive pyothorax-associated lymphoma (PAL) is a prototype of DLBCL-CI and represents a valuable model for the study of this disease category. Using a panel of PAL cell lines, we found that PAL cells expressed and secreted C-X-C motif chemokine ligands 9 and 10 (CXCL9 and CXCL10), the ligands of CXCR3, in contrast to EBV-negative DLBCL cell lines, which did not. Culture supernatants from PAL cell lines attracted CXCR3-expressing CD4+ T cells, CD8+ T cells, and CD56+ natural killer cells from human peripheral blood mononuclear cells. PAL cells injected into mice also attracted CXCR3-positive cytotoxic lymphocytes that expressed interferon-γ. The expression of CXCL9 and CXCL10 was detected in PAL tumor biopsy samples from patients, and CXCR3-positive lymphocytes were abundant in the tissue samples. Collectively, these findings suggest that CXCL9 and CXCL10 are produced by PAL cells and can elicit cytotoxic responses via CXCR3. This chemokine system is also likely to contribute to tissue necrosis, which is a signature histological feature of DLBCL-CI. Further studies are warranted to determine whether the CXCL9-CXCL10/CXCR3 axis exerts antitumor effects in DLBCL-CI.

Chest wall fistula in a patient with pyothorax-associated lymphoma.

Key messageFistula formation is an uncommon but serious therapeutic complication of pyothorax‐associated lymphoma (PAL) because it decreases the quality of life in patients. Furthermore, a collapsed lung may predispose to pneumonia. In PAL, the lesions might invade the skin and optimal irradiation dose, region, and timing should be carefully determined.

Characterization of Artificial Pneumothorax-Unrelated Pyothorax-Associated Lymphoma.

Pyothorax-associated lymphoma (PAL) is a rare disease developing from a long-term pleural cavity inflammation. Most reported PAL cases have a history of artificial pneumothorax. However, the clinical features of artificial pneumothorax-unrelated PAL remain largely unknown. Here, we reported two PAL cases diagnosed from our center in the past ten years. One case developed from asymptomatic pyothorax after pneumonectomy with a latency of 28 years, while the other case showed a relatively short latency of one year. Then we reviewed the literature of artificial pneumothorax-unrelated PAL by searching PubMed and Google Scholar from 2007. In total, nine artificial pneumothorax-unrelated PAL cases were found, predominantly in old male with median age of 76 years (ranging from 51 to 88). Most cases were diagnosed with diffuse large B-cell lymphoma (DLBCL) (n = 8, 88.9%) and had evidence of Epstein-Barr virus (EBV) infection (n = 6, 66.7%) or tuberculous pleurisy (n = 5, 55.6%). Notably, four cases (44.4%) had short intervals (no more than two years) between pleuritis and PAL. Regarding the overall survival, one-third cases survived more than 5 years after the diagnosis of PAL. In conclusion, the features of artificial pneumothorax-unrelated PAL are comparable with the classic type of PAL, except for some patients with short duration of pleuritis, and need to be identified. Treatment guideline of DLBCL is recommended for the management of PAL.

RARE CAUSE OF PLEURAL EFFUSION

SESSION TITLE: Fellows Lung Cancer Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Primary pleural lymphomas (PPL) represent 7% of lymphomas. Most are of B cell origin, and related to immunosuppression or chronic inflammation. [1, 2]. Anaplastic large cell lymphoma is a rare CD30 positive T cell lymphoma [3]. CASE PRESENTATION: A 73-year-old patient with a past medical history of end-stage renal disease on peritoneal dialysis presented to the emergency department with complaints of dry cough and shortness of breath of two weeks course. He also reported poor appetite and unintentional weight loss over three months prior to his presentation. Physical exam was significant for tachycardia, tachypenia, and oxygen saturation of 92% on 3 liters nasal cannula. Reduced breath sounds on the right hemithorax. His laboratory tests showed hemoglobin of 10.6 gm/dl, serum creatinine of 11 mg/dl. CT of the chest showed a loculated right hydropneumothorax without pleural thickening. A chest tube was placed, and fluid was sent to for analysis. Pleural fluid analysis showed a PH 7.45, lactate dehydrogenase (LDH) 1580 U/l, albumin 1.9 g/dl, no organism was detected. Flow cytometry from the fluid was normal. A pleural biopsy showed CD 30, CD4, MUM1 positive T cell lymphoma and negative for human herpesvirus-8 (HHV-8), ALK, and Myeloperoxidase (MPO). Further staging CT showed no lymphadenopathy, hepatosplenomegaly or any other masses. A diagnosis of primary effusion anaplastic large cell lymphoma, ALK-negative was made and he was started on Brentuximab Vedotin. DISCUSSION: PPL are very uncommon and classified into two different types: i) Primary effusion lymphoma (PEL) related to HIV infection and HHV-8. ii) Pyothorax-associated lymphoma (2.2% of the cases) mainly related to chronic inflammation as in tuberculosis and asbestosis, they are described as B cell non-Hodgkin lymphoma. Pleural T cell lymphomas are quite rare. Few cases are reported in immune-competent patients in the absence of a prior history of pyothorax. Anaplastic large cell lymphoma (ALCL) is a rare CD 30 positive T cell lymphoma. The 2016 revision of the WHO classification divided ALCL in to three subtypes of a) ALK positive (ALK+) ALCL, b) ALK negative (ALK-) ALCL and c) breast implant-associated ALCL Treatment includes chemotherapy, typically cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), and CD30-targeted brentuximab vedotin, as The ECHELON- 2 trial showed the combination of Brentuximab with chemotherapy was found to be superior to CHOP CONCLUSIONS: PPLs are extremely rare. Two distinct sub-types exist: PEL in immunosuppressed patients, and pyothorax associated lymphoma with long standing inflammations as in Tuberculosis. The majority of the cases are of B cell origin, with a few reports reporting instances in T cell lymphoblastic lymphoma of the pleura. Anaplastic large cell lymphoma causing primary pleural effusion has not been described in the literature. Reference #1: 1.Alexanian S, Said J, Lones M, Pullarkat ST. KSHV/HHV8-negative Effusion-based Lymphoma, a Distinct Entity Associated With Fluid Overload States. The American Journal of Surgical Pathology 2013;37:241–9. doi:10.1097/pas.0b013e318267fabc. Reference #2: 2.Sun M-L, Shang B, Gao J-H, Jiang S-J. Rare case of primary pleural lymphoma presenting with pleural effusion. Thoracic Cancer 2015;7:145–50. doi:10.1111/1759-7714.12256. Reference #3: 3.Carbone A, Gloghini A. PEL and HHV8-unrelated effusion lymphomas. Cancer 2008;114:225–7. doi:10.1002/cncr.23597. DISCLOSURES: No relevant relationships by Amani Erra, source=Web Response no disclosure on file for Karim Fahmy; No relevant relationships by Mahmoud Khreis, source=Web Response No relevant relationships by Mohanad Soliman, source=Web Response

Imaging Features of Various Benign and Malignant Tumors and Tumorlike Conditions of the Pleura: A Pictorial Review.

Pleural masses may be caused by various conditions, including benign and malignant neoplasms and non-neoplastic tumorlike conditions. Primary pleural neoplasms include solitary fibrous tumor, malignant mesothelioma, and primary pleural non-Hodgkin's lymphoma. Metastatic disease is the most common neoplasm of the pleura and may uncommonly occur in patients with hematologic malignancy, including lymphoma, leukemia, and multiple myeloma. Pleural effusion is usually associated with pleural malignancy. Rarely, pleural malignancy may arise from chronic empyema, and the most common cell type is non-Hodgkin's lymphoma (pyothorax-associated lymphoma). Non-neoplastic pleural masses may be observed in several benign conditions, including tuberculosis, pleural plaques caused by asbestos exposure, and pleural loose body. Herein, we present a review of benign and malignant pleural neoplasms and tumorlike conditions with illustrations of their computed tomographic images.

Primary Mediastinal Nodal and Extranodal Non-Hodgkin Lymphomas: Current Concepts, Historical Evolution, and Useful Diagnostic Approach: Part 1

Primary mediastinal non-Hodgkin lymphomas (PM-NHLs) represent ~5% of all NHLs and comprise lymphomas of B-cell and T-cell origin. PM-NHLs are defined as involvement of mediastinal lymph nodes, thymus, and/or mediastinal organs (heart, lung, pleura, pericardium) by NHL without evidence of systemic disease at presentation. The clinical scenario is variable and depends on the lymphoma subtype. The radiologic presentation is also variable ranging from a mediastinal mass with or without superior vena cava syndrome, a pleural or a cardiac mass associated with an effusion, or as an effusion only. The diagnosis of PM-NHLs can only be established by microscopic evaluation, and therefore, general pathologists should be aware of these tumors and familiar with their diagnostic approach. The most common anterior mediastinal NHLs (90% to 95%) are primary mediastinal large B-cell lymphoma and T lymphoblastic lymphoma. Thymic marginal zone lymphoma and mediastinal gray zone lymphoma are very rare. The remainder PM-NHLs involving middle or posterior mediastinum include diffuse large B-cell lymphoma (DLBCL) and rare cases of T-cell lymphoma, including anaplastic large cell lymphoma and breast implant-associated anaplastic large cell lymphoma extending to the anterior mediastinum. Primary pleural and cardiac NHLs are mostly DLBCLs. Other rare subtypes of PM-NHLs include DLBCL associated with chronic inflammation/pyothorax-associated lymphoma, fibrin-associated DLBCL (both EBV), and pleural and/or pericardial primary effusion lymphoma (HHV-8/EBV). We review the historical aspects, epidemiology, clinico-radiologic features, histopathology, immunohistochemistry, differential diagnosis, and relevant cytogenetic and molecular features of PM (thymic) LBCL, PM "nonthymic" DLBCL, BCL, unclassifiable, with features intermediate between DLBCL and classic Hodgkin lymphoma (mediastinal gray zone lymphoma), DLBCL associated with chronic inflammation (pyothorax-associated lymphoma), fibrin-associated DLBCL, and primary effusion lymphoma. This review represents the first part of 2 manuscripts covering PM-NHLs.

Epstein-Barr virus-positive pyothorax-associated lymphoma expresses CCL17 and CCL22 chemokines that attract CCR4-expressing regulatory T cells.

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphomas associated with chronic inflammation (DLBCL-CI) develop in patients with chronic inflammation but without any predisposing immunodeficiency. Given the expression of the EBV latent genes, DLBCL-CI should have mechanisms for evasion of host antitumor immunity. EBV-positive pyothorax-associated lymphoma (PAL) is a prototype of DLBCL-CI and may provide a valuable model for the study of immune evasion by DLBCL-CI. This study demonstrates that PAL cell lines express and secrete CCL17 and/or CCL22 chemokines, the ligands of C-C motif chemokine receptor 4 (CCR4), in contrast to EBV-negative DLBCL cell lines. Accordingly, culture supernatants of PAL cell lines efficiently attracted CCR4-positive regulatory T (Treg) cells in human peripheral blood mononuclear cells. PAL cells injected into mice also attracted CCR4-expressing Treg cells. Furthermore, this study confirmed that CCR4-expressing Treg cells were abundantly present in primary PAL tissues. Collectively, these findings provide new insight into the mechanisms of immune evasion by PAL, and further studies are warranted on whether such mechanisms eventually lead to the development of DLBCL-CI.

When to use in situ hybridization for the detection of Epstein-Barr virus: a review of Epstein-Barr virus-associated lymphomas

Epstein-Barr (EBV) is the first virus supposed to be causative for human neoplasm. To date, list of EBV-associated lymphomas includes Burkitt lymphoma, Hodgkin lymphoma, pyothorax-associated lymphoma, primary effusion lymphoma, nasal type extranodal natural killer/T cell lymphoma, plasmablastic lymphoma, immunodeficiency-associated lymphoproliferative disorders, and lymphomatoid granulomatosis. In these diseases, presence of EBV could be detected at protein level by immunohistochemistry and at genetical level by polymerase chain reaction and in situ hybridization both applicable on routinely processed formalin-fixed, paraffin-embedded specimens. Clonality of EBV-infected cells could be examined by Southern blot analysis. EBV status examined using these ancillary diagnostic tools were informative for diagnosis of lymphoma, especially diseases developing under immunodeficient condition and diseases showing polymorphous histology with or without large multinucleated cell like a Hodgkin–Reed Sternberg cell. Comprehensive evaluation of clinical presentation, histology, immunohistochemistry, genetic aberration, and EBV status enable accurate diagnosis of EBV-associated lymphoma.

Pyothorax-associated lymphoma (PAL) with biclonal Epstein–Barr virus infection: Characterization of a novel PAL cell line with unique features

Pyothorax-associated lymphoma (PAL) is a representative form of diffuse large B-cell lymphoma associated with chronic inflammation, in which the Epstein-Barr virus (EBV) genome is consistently detectable in the lymphoma cells of all PAL cases. Cell lines and animal models would be useful for understanding better this rare lymphoma, but reports of PAL-derived cell lines are scarce. We report a new PAL cell line, designated Pal-2, with unique phenotypic expression. Pal-2 is the first PAL cell line that carries a biclonal EBV infection with abundant viral genome and that exhibits tumorigenic capacity once injected into nude mice.

Pyothorax-associated lymphoma: complete remission achieved by chemotherapy alone

We present the case of a patient with malignant lymphoma resulting from chronic pyothorax after artificial pneumothorax for pulmonary tuberculosis. The 81-year-old female patient had a medical history of artificial pneumothorax from left pulmonary tuberculosis when she was 23 years old and subsequent chronic pyothorax. She had become aware of pain in the left back from October 2008. Chest computed tomography revealed a tumor measuring 61 mm × 27 mm behind the left sixth and seventh ribs. After biopsy revealed pyothorax-associated lymphoma, 4 courses of R-CHOP therapy were administered, leading to complete remission. No recurrences were noted during follow-up over a 4-year period after the initiation of therapy.

A20 (TNFAIP3) Deletion in Epstein-Barr Virus-Associated Lymphoproliferative Disorders/Lymphomas

A negative regulator of the nuclear factor (NF)-κB pathway, A20 (TNFAIP3), is inactivated in several types of lymphomas; particularly in diffuse large B-cell lymphoma (DLBCL), classical Hodgkin's lymphoma, and extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue. These findings suggest that the NF-κB activation is related to A20 inactivation. Recently, A20 inactivation has also been observed in Epstein-Barr virus (EBV)-related lymphomas; however, this occurrence has not been well investigated. Moreover, NF-κB is a key molecule in activated B-cell-like (ABC)-type DLBCL; EBV-associated DLBCL is of the ABC type. Therefore, we focused on A20 deletions in EBV-associated lymphoproliferative disorders/lymphomas. Using fluorescent in situ hybridization analysis, A20 deletions were identified in 4 of 13 samples from patients with pyothorax-associated lymphoma (PAL) (31%), 3 of 20 samples from nasal-type NK/T cell lymphomas (NKTLs) (15%), 1 of 8 samples of EBV-positive DLBCL of the elderly (DLBCL-e) (13%), but not in any of the 11 samples from individuals with methotrexate-related lymphoproliferative disorder (MTX-LPD) (0%). Among the samples with A20 deletions, EBV latent membrane protein 1 (LMP-1) expression was detected in all 4 of the PAL samples with A20 deletions and in the DLBCL-e sample with an A20 deletion, but not in any of the 3 NKTL samples. This finding indicated that A20 deletions were not directly related to the EBV latency pattern of lymphomas, although such deletions might be related to the diagnostic category. Immunohistologically, the A20 protein was absent in 2 (15%) of the13 PAL samples, 1 (9%) of 11 MTX-LPD samples, and in none of the 20 NKTL (0%) or 8 DLBCL-e samples. In conclusion, A20 deletion and/or dysfunctional expression are frequently associated with PALs, and A20 abnormalities may be related to the pathogenesis of PAL.

Microscopic Diffuse Large B-Cell Lymphoma (DLBCL) Occurring in Pseudocysts

We report 2 cases of localized, microscopic diffuse large B-cell lymphoma (DLBCL) that were detected incidentally within pseudocysts. In case 1, the neoplasm was identified within a 26-cm, 860-g adrenal gland pseudocyst. In case 2, the neoplasm was detected within a 9-cm, 90-g paratesticular pseudocyst. In both cases, the neoplastic cells were large, had a nongerminal center B-cell immunophenotype, and were positive for Epstein-Barr virus (EBV)-encoded RNA detected by in situ hybridization. The most appropriate classification of these tumors using current World Health Organization classification is uncertain. The best fit seems to be DLBCL associated with chronic inflammation (DLBCL-CI), defined as DLBCL arising in the context of long-standing chronic inflammation and associated with EBV infection, with the prototype for this category being pyothorax-associated lymphoma. This term has been used by others in the literature for tumors similar to the cases reported here. However, in the 2 cases we report chronic inflammation was not a prominent feature, and the inflammatory cells that were present showed little relationship to the lymphoma cells. The findings in these cases have led us to question the role of chronic inflammation in pathogenesis. Perhaps the closed space of the pseudocyst, by preventing a cytolytic response to EBV-infected cells, results in local immunodeficiency that may be most important for pathogenesis. We also have concerns about using the term DLBCL-CI for these tumors. Perhaps the cases we report and the few other similar cases reported previously deserve their own category in a future version of the World Health Organization classification.

捺印細胞診にて推定しえた EB ウイルス陽性 T 細胞性膿胸関連リンパ腫の 1 例

背景 : 膿胸関連リンパ腫は, 肺結核性慢性膿胸や肺結核治療としての人工気胸術後の慢性膿胸壁に発生する悪性リンパ腫である. 大部分は B 細胞性であり T 細胞性はまれである. 今回われわれは胸壁腫瘤捺印細胞診にて推定しえた EB ウイルス陽性 T 細胞性膿胸関連リンパ腫の 1 例を経験したので報告する.症例 : 86 歳, 男性. 27 歳時に肺結核に対して左人工気胸術を受けた. 2009 年になり左季肋部痛が出現し近医を受診, 慢性膿胸と胸壁腫瘤を指摘され, 当院を紹介受診した. 診断目的に施行された胸壁腫瘤の切開生検時の捺印細胞診では, 細胞形態ならびに免疫細胞化学染色の結果を総合的に判断して EB ウイルス陽性 T 細胞性リンパ腫を推定した. また, 病理組織所見, 免疫組織化学所見から peripheral T-cell lymphoma, not otherwise specified と確定診断した.結論 : 膿胸関連リンパ腫のなかでも非常にまれな T 細胞性を経験した. 捺印細胞診においても積極的に免疫細胞化学染色を併用することで, リンパ腫のタイプや EB ウイルス感染の有無を推定することができた貴重な症例と考える.

Prognostic impact of extranodal involvement in diffuse large B‐cell lymphoma in the rituximab era

Extranodal involvement is considered a poor prognostic factor for patients with diffuse large B-cell lymphoma (DLBCL); however, the prognostic impact of specific sites of involvement has not been fully elucidated. The authors retrospectively analyzed 1221 patients treated uniformly with standard R-CHOP therapy between 2003 and 2006. Patients with distinct forms of DLBCL such as intravascular lymphoma, primary effusion lymphoma, pyothorax-associated lymphoma, primary central nervous system lymphoma, and intraocular lymphoma were also excluded. The authors evaluated 26 extranodal sites of involvement with respect to prognostic impact. The median age was 64 years (range, 15-91 years). Univariate analysis revealed that patients with involvement of specific extranodal sites had significantly worse overall survival (OS) than did patients without such involvement; these sites included nasal cavity, paranasal sinus, lung, pleura, small intestine, peritoneum, liver, pancreas, stomach, spleen, adrenal gland, testis, bone, bone marrow, peripheral blood, skin, and subcutaneous tissue. Patients with Waldeyer ring involvement had significantly better OS. Multivariate analysis revealed that patients with the involvement of the pleura (P < .001), small intestine (P = .015), peritoneum (P = .002), adrenal gland (P < .001), testis (P = .005), bone marrow (P < .001), and peripheral blood (P = .002) had significantly worse OS, whereas those with Waldeyer ring involvement had significantly better OS (P = .038). Subgroup analysis with the nodal and/or Waldeyer patient group also showed prognostic impact of Waldeyer ring by multivariate analysis (relative risk, 0.3; P = .04). Extranodal involvement affects the prognosis of patients undergoing R-CHOP therapy for DLBCL.

Thoracic malignancies in patients with chronic tuberculous empyema

To clarify features of thoracic malignancies occurred in patients with chronic tuberculous empyema. We analyzed clinicopathological data of 15 patients with thoracic malignancies who had chronic tuberculous empyema, encountered at Tokyo National Hospital during the period from 1977 to 2002. There were 13 men and 2 women, with a mean age of 67 years. Most of all (13/15) patients had history of surgery for tuberculosis including artificial pneumothorax (9 cases). Malignancies consisted of pyothorax-associated lymphoma (PAL; 9 cases), lung cancer (4 cases), malignant fibrous histiocytoma (1 case), and angiosarcoma (1 case). There were no differences in background factors between PAL patients and the other patients. Common symptoms were chest pain (10 cases), fever (7 cases), and bloody sputum (4 cases) and it seemed that these symptoms were more evident in patients with PAL than in patients with other diseases. Plain chest X-ray films often failed to detect the tumor, and the diagnosis was often obtained by sputum cytology, bronchofiberscopy, transcutaneous biopsy, and resection with support of CT and/or MRI films. On radiographs, all tumors located in empyema cavities or around empyema walls, and a pulmonary mass adjacent to the empyema wall was characteristic of lung cancer. PAL showed certainly good outcome; 40% 5-year survival rate with resection or chemoradiotherapy. On the other hand, all of lung cancer cases were diagnosed at stage III, and had poor outcome, and the remaining patients with the other malignancies also had poor outcome. Clinicians should keep in mind occurrence of several thoracic malignancies during the follow-up of patients with chronic tuberculous empyema.

Prognostic impact for different sites of extranodal involvement in patients with diffuse large B-cell lymphoma in the rituximab era.

e18505 Background: Extranodal involvement is considered poor prognostic factor for patients with diffuse large B-cell lymphoma (DLBCL); however, the prognostic impact of each involvement site has not yet been fully elucidated. Methods: We retrospectively analyzed data for 1,221 patients with DLBCL uniformly treated by R-CHOP therapy between 2003 and 2006. Patients with distinct forms of DLBCL, such as intravascular lymphoma, primary effusion lymphoma, and pyothorax-associated lymphoma, were excluded from the study. Primary CNS lymphoma and intraocular lymphoma were also excluded. We evaluated 26 extranodal involvement sites (orbita, nasal cavity, paranasal sinus, Waldeyer ring, salivary gland, thyroid gland, breast, thymus, lungs, pleura, stomach, small intestine, colon, peritoneum, liver, pancreas, kidney, spleen, adrenal gland, testes, ovary/uterus, bones, bone marrow, peripheral blood, skin, and subcutaneous tissue) with respect to prognostic impact. Results: The median age was 64 years (range, 15–91 years). Nine hundred and ten patients (74.6%) were treated with 6-8 cycles of therapy. Local irradiation was added in 297 patients (24.4%). Univariate analysis revealed that the patients with certain extranodal involvement had significantly worse overall survival (OS) than did the patients without the extranodal involvement; these sites included nasal cavity, paranasal sinus, lungs, pleura, small intestine, peritoneum, liver, pancreas, stomach, spleen, adrenal gland, testes, bones, bone marrow, peripheral blood, skin, and subcutaneous tissue. Patients with Waldeyer ring involvement had significantly better OS. Multivariate analysis revealed that patients with involvement of pleura (P < 0.001), small intestine (P = 0.015), peritoneum (P = 0.002), adrenal gland (P < 0.001), testes (P = 0.005), bone marrow (P < 0.001), and peripheral blood (P = 0.002) had significantly worse, but Waldeyer ring had significantly better OS (P = 0.038). Conclusions: Extranodal involvement affects the prognosis of patients undergoing R-CHOP therapy for DLBCL. Waldeyer ring involvement may be a better prognosis factor.

A mass originating from chronic pyothorax in the pleural cavity

A 71-year-old male with a past history of tuberculous pleuritis was referred to our hospital in 2008 because of right chest pain. Chest computed tomography (CT) demonstrated a huge mass originated from chronic pyothorax in the right pleural cavity, invading the chest wall. 2-[F]fluoro-2-deoxy-D-glucose Positron Emission Tomography (FDG-PET) imaging showed strong uptake only in the tumor of the right chest wall (Image 1A). Immunohistochemical staining and Southern blot hybridization of biopsied specimens revealed that the diagnosis was CD20 negative pyothorax-associated diffuse large B cell lymphoma. In situ hybridization for Epstein-Barr virus (EBV) disclosed EBV-encoded small RNA expression in the lymphoma cells. Clinical stage was IE, and international prognostic index was low intermediate. First, three courses of pirarubicin-cyclophosphamide, vincristine, prednisolone (COP) were administered. Then confirming that FDG-PET became negative (Image 1B), involved-field radiotherapy of 50 Gy was added. No sign of relapse has been found for more than 2 years. Pyothorax-associated lymphoma (PAL) is defined as nonHodgkin’s lymphoma of exclusively B-cell phenotype developing in the pleural cavity of patients with chronic pyothorax [1,2]. Most of PAL cases express CD20; however, there are a small proportion of cases which do not express B cell antigens such as CD20 and CD79a [3,4]. It is suggested that PAL is strongly associated with EBV [5,6]. A mass in the pleural cavity with a history of tuberculosis should cause one to consider PAL in the differential diagnosis.

A Case of Pyothorax Associated Lymphoma Positive for Epstein-Barr Virus Developing from Chronic Empyema

症例は81歳男性. 肺結核の既往あり陳旧性結核性胸膜炎との診断で近医にて経過観察されていた. 2010年12月下旬より咳嗽・胸部不快感・食欲不振が出現し, 2011年1月7日近医を受診した. 胸部単純写真にて浸潤影を認め肺炎が疑われ当院に紹介入院した. 胸腹部造影CTにて右胸腔内に巨大な空洞性病変を認め, 薄く造影される壁は不整な結節状に肥厚し内腔に液体貯留を認めた. 腫瘤は空洞壁に沿って認められ, 多発膿瘍・転移性腫瘍・悪性胸膜中皮腫・原発性肺癌などが考えられた. 組織学的検索などの精査を実施しつつ肺炎・膿胸の合併を考え抗生剤投与を施行していたが全身状態悪化にて死亡した. 死亡後, 病理解剖を施行し膿胸関連悪性リンパ腫と診断された. 組織学的には核内にEBER (EBV encoded small RNAs) 陽性所見を伴うびまん性大型B細胞性リンパ腫の所見を示しており, EBウイルスの感染を確認できたことより発症にEBウイルスが関与した典型的な一例と考えられた. 経過が長い慢性膿胸の存在する患者に胸部不快感, 肺炎様症状, 炎症反応, 胸壁腫瘤が認められる場合, 膿胸関連悪性リンパ腫の存在を念頭に入れる必要があると考えられ若干の文献的考察を加えて報告する.

Central Nervous System Events In Patients with Diffuse Large B-Cell Lymphoma In the Rituximab Era

AbstractAbstract 3948 Background:The central nervous system (CNS) is considered a sanctuary because drugs at standard doses rarely reach it. CNS event is defined as disease recurrence in the CNS during complete systemic remission or CNS progression as concurrent disease in the CNS during active systemic disease. These CNS events are associated with extremely poor patient prognosis. To evaluate the risk of CNS events in patients with diffuse large B-cell lymphoma (DLBCL) in the rituximab (R) era, we performed a retrospective study with a large cohort in Japan. Materials and Methods:All patients were diagnosed as having DLBCL and underwent primary therapy from September 2003 to December 2006. Patients with distinct forms of DLBCL, such as intravascular lymphoma, primary effusion lymphoma, and pyothorax-associated lymphoma were excluded. Those who had received any prophylactic CNS treatment; and those with CNS involvement at the beginning of therapy were also excluded. Primary therapy comprised standard R-CHOP therapy or R-THP-COP therapy (pirarubicin instead of doxorubicin hydrochloride). CNS involvement was considered when malignant cells were detected in cytocentrifuged preparations of cerebrospinal fluid (leptomeningeal type) and/or when an intracranial or spinal mass was detected by radiologic imaging such as computed tomography or magnetic resonance imaging (parenchymal type). Results:(1) Baseline characteristics. Clinical data from 1,492 patients were collected from 48 institutions. The median age was 67 years (range, 15–93 years). R-CHOP therapy was administered in 1,227 patients (82.2%) and R-THP-COP therapy, in 265 patients (17.8%). Therapy for 6–8 cycles was administered to 1099 patients (73.7%). Local irradiation was included for 344 patients (23.1%). The 5-year overall survival (OS) rate in the entire cohort was 72.8%, and the median observation period for the surviving patients was 47.6 months. (2) Incidence of CNS events. In total, 94 CNS events (6.3%) were recorded. More than half were of the parenchymal type (57.4%); the rest were mostly of the leptomeningeal type (29.8%), and some were of both types (12.8%). The events occurred during the first complete remission (CR) in 40 patients (42.6%) and in the second or later CR in 11 patients (11.6%). Death from any cause was recorded in 64 of the 94 patients (68.1%) during the observation period, and most deaths were due to lymphoma. The cumulative 5-year probability of CNS events was 8.0%. (3) Risk factors for CNS events. Multivariate Cox regression analysis identified involvement of the breast (relative risk (RR), 7.9), adrenal gland (RR, 3.3), paranasal sinus (RR, 2.9), and bone (RR, 2.3). as risk factors for CNS events. Time to CNS event curves differed significantly between patients with and without CNS risk sites (P < 0.001). (4) Survival after CNS events. Patients with CNS events demonstrated significantly poorer OS (P < 0.001). The 2-year OS rate after a CNS event was 25.7%, and the 50% survival duration was 4.6 months. No significant differences were observed between any 2 of the 3 types of CNS events. Depending on the systemic lymphoma status at the time of the CNS events, patients in first CR showed better survival than the others (P = 0.019). Patients in any CR also showed superior survival than those not in CR (P = 0.015). Conclusions:We concluded that DLBCL patients in the R era with any of these risk factors (breast, adrenal gland, paranasal sinus, or bone involvement), in addition to patients with testicular involvement in whom CNS prophylaxis has been already justified, are at high risk for CNS events. The efficacy and manner of CNS prophylaxis for each involvement sites should be evaluated further. Disclosures:No relevant conflicts of interest to declare.

Increased Peripheral T Cell Responses to EBV-Infected Cells with Frequent Detection of EBV-DNA In Plasma and Viral mRNA In Peripheral B-Cells In Immunocompetent EBV-Positive Diffuse Large B-Cell Lymphoma Patients

AbstractAbstract 4163 Introduction:It is well known that immunocompromised patients(pts) such as post-transplantation or HIV infection are at increased risk of EBV-associated B-cell lymphoproliferaitive disorders. However, the immunological status of immunocompetent EBV-positive diffuse large B-cell Lymphoma (DLBCL) has not been well elucidated. For example, EBV-positive DLBCL in the elderly is defined as an EBV-positive clonal B-cell lymphoid proliferation occurring in pts more than 50 years of age and without any known immunodeficiency in WHO classification 2008, accounting for 5 – 10% of DLBCL in Japan. This disease is speculated to be related to the immunological deterioration accompanying the aging process. We conducted a multi-center prospective study to assess EBV status and the T cell response to EBV of peripheral blood (PB) in EBV-positive DLBCL in comparison with EBV-negative DLBCL pts and normal old-healthy persons (old-HPs). Patients and Methods:Fifteen newly-diagnosed pts with EBV-positive DLBCL, 8 pts with EBV-negative DLBCL, and 16 old-HPs were enrolled. Median ages of pts with EBV-positive DLBCL, pts with EBV-negative DLBCL, and old-HPs were 74.5 years (range 29–82 years), 71 years (48-79), and 65 years (60-74), respectively. Among the 15 pts with EBV-positive DLBCL, 2 were pyothorax-associated lymphoma, 2 were treated with methotrexate for rheumatoid arthritis, and the remaining 11 pts were without past histories predisposing to immunodeficiency. The diagnosis of EBV-positive DLBCL was made by positive signals for in situ hybridization using EBV-encoded small RNA (EBER) on paraffin section. To analyze T cell reactivity to autologous EBV-infected B-cell lymphoblastoid cell lines (LCL), CFSE-labeled peripheral blood mononuclear cells (PBMCs) were co-cultured with irradiated autologous LCL, and the division indices (DI) of CD4+ and CD8+ T cells were determined on day 5 (Cytometry 34:143, 1998). Percentage of proliferating CFSElow IFN-γ+CD4+ T cells and CFSElow IFN-γ+CD8+ T cells was assessed on day 7. EBV DNA load in PBMCs and plasma was determined by quantitative real-time PCR. CD19+ B cells were separated from of PBMCs by immunomagnetic sorting, and viral mRNA expression of B cells was quantified by one-step multiplex real-time RT-PCR. Results:(1) Plasma EBV-DNA was detectable in 13 of the 15 EBV-positive DLBCL pts but in none of the 8 EBV-negative DLBCL pts or the 16 old-HPs. Copy number of EBV-positive DLBCL was significantly higher than EBV-negative DLBCL (p<0.00001) or old-HPs (p=0.0001). EBV-DNA in PBMC was positive in 10 of the 15 EBV-positive DLBCL pts, 2 of 8 EBV-negative DLBCL pts, and 2 of 15 old-HPs. (2) EBER1 of PB B cells was detected in all 10 EBV-positive DLBCL pts, 4 of 7 EBV-negative DLBCL pts, and 7 of 14 old-HPs. BamHI A rightward transcripts (BARTs) of B-cells was detected in 8 of 10 EBV-positive DLBCL pts, 3 of 10 EBV-negative DLBCL pts, and 2 of 14 old-HPs. Latent membrane protein 2 (LMP2) of B cells was detected in 2 of 10 EBV-positive DLBCL pts, 2 of 14 old-HPs, and none of 5 EBV-negative DLBCL pts. LMP1 of B cells was detected in 1 of 10 EBV-positive DLBCL pts, none of 7 EBV-negative DLBCL pts, and none of 14 old-HPs. EBV-encoded nuclear antigen 1 (EBNA1) or EBNA2 were not detected in any of the pts nor old-HPs. (3) DI of CD4+ T cells for 5 days in EBV-positive DLBCL (median 1.41) was significantly higher than in old-HPs (median 0.53) (p=0.0009), and DI of CD8+ T cells of EBV-positive DLBCL (median 1.94) showed a higher tendency than old-HP (median 1.35). (4) Percentage of CFSE-low IFN-γ+CD4+ T cells in EBV-positive DLBCL (median 9.8%) was significantly higher than in old-HPs (median 2.2%) (p=0.002), and percentage of CFSE-low IFN-γ+CD8+ T cells in EBV-positive DLBCL (median 12.0%) was significantly higher than in old-HPs (median 6.6%)(p=0.025). Conclusions:Measurement of the plasma EBV-DNA copy number is a good indicator for the diagnosis of EBV-positive DLBCL, and the frequent detection of EBV viral mRNA of peripheral B-cells in EBV-positive DLBCL pts might be associated with greater viral load. Proliferative and INF-γ secreting responses of both peripheral CD4+ T cells and CD8+ T cells to EBV-infected cells were increased in EBV-positive DLBCL compared to old-HPs, which might be driven by an elevated viral load. These findings suggest that systemic immunological reaction to EBV might be intact in EBV-positive DLBCL. Disclosures:No relevant conflicts of interest to declare.