Case Of Pyothorax-associated Lymphoma Research Articles

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.

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.

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.

F-18 FDG PET/CT Findings in Two Patients With Pyothorax-Associated Lymphoma

We report 2 cases of pyothorax-associated lymphoma that underwent F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) examinations during pre- and post-treatment states. The FDG PET/CT examinations were able to define the massive lesions as areas of intensive FDG uptake. After radiotherapy, follow-up PET/CT examinations showed the disappearance of the abnormal FDG uptake, although the residual masses remained in the original regions. Finally, we concluded that these lesions had entered remission based on the PET/CT findings. These cases indicate that PET/CT is a useful modality for detecting pyothorax-associated lymphoma and for evaluating the efficacy of treatments.

Usefulness of 18F-FDG positron emission tomography/computed tomography for the diagnosis of pyothorax-associated lymphoma: A report of three cases

Pyothorax-associated lymphoma (PAL) is a unique and rare non-Hodgkin's lymphoma developing in the pleural cavity following a long-standing history of chronic pyothorax (CP). The development of F-18 2'-deoxy-2fluoro-D-glucose (FDG) positron emission tomography combined with computed tomography (PET/CT) has contributed to the evaluation of lymphoma staging. However, only a few studies describing FDG-PET/CT findings in PAL have been published. This study reported three cases of PAL; all 3 patients had previously undergone artificial collapse therapy for pulmonary tuberculosis. Both the first case (an 84-year-old male) and second case (an 83-year-old male) complained of abdominal pain. An ultrasound scan revealed a mass shadow in the left chest wall without abnormal findings in the abdomen, and the CT and magnetic resonance imaging scans suggested malignant lymphoma of the left chest. FDG-PET/CT imaging showed extremely intense FDG uptake only in the left pleura and chest wall. Diagnosis was CP in the two patients, showing a high maximum standardized uptake value (SUVmax: early, 14.8 and delayed, 19.4 in the first case; early, 20.8 and delayed, 27.3 in the second case, respectively). Histopathological analysis of the specimens obtained by biopsy of the PET/CT-positive pleural mass showed non-Hodgkin's, diffuse large B cell lymphoma in the two cases. The third case was a 79-year-old male with relapse after right pleuropneumonectomy for PAL (diffuse large B cell lymphoma) 4 years earlier. PET/CT showed intense FDG uptake (SUVmax: early, 19.9 and delayed, 35.7) in the right pleura and chest wall. Diagnosis was CP, suggesting the recurrence of PAL. Furthermore, abnormal intense FDG uptake was noted in the hilar, mediastinal and supraclavicular lymph nodes, as well as in the spleen. In conclusion, FDG-PET/CT imaging is useful in the evaluation of the area of invasion in PAL.

Loss of expression of Epstein‐Barr virus nuclear antigen‐2 correlates with a poor prognosis in cases of pyothorax‐associated lymphoma

Pyothorax-associated lymphoma (PAL) is a non-Hodgkin's lymphoma, which develops in the pleural cavity of patients who have had pyothorax for over 20 years, and is strongly associated with Epstein-Barr virus (EBV) infection. The expression of latent genes, especially EBV nuclear antigen-2 (EBNA-2), influences the growth characteristics and malignant features of EBV-infected cells. Here, the effect of EBNA-2 expression on clinical features was examined in 13 cases of PAL. The EBNA-2 transcript was detected in 8 cases but was absent in 5. There was a significant difference in survival between patients with the transcripts and those without: the 1-year survival rate was 87.5 and 0%, respectively (p < 0.01). There was a discrepancy between EBNA-2 expression and EBNA promoter usage in 6 cases. The Cp/Wp promoter was used in 3 EBNA-2-negative cases, whereas the Qp promoter or multiple promoters were used in 3 EBNA-2-positive cases. Analysis of PAL cell lines provided a clue as to the mechanism underlying the discrepancy between EBNA-2 expression and EBNA promoter usage. Loss of EBNA-2 expression, irrespective of the latency pattern, is correlated with a poor prognosis, suggesting that down-regulation of the EBNA-2 expression could be selection pressure for the progression of PAL.

Usefulness of FDG-PET imaging for the radiotherapy treatment planning of pyothorax-associated lymphoma

Pyothorax-associated lymphoma (PAL) is a non-Hodgkin's lymphoma developing in the pleural cavity after a long-standing history of chronic pyothorax (CP). F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging is a useful modality for determination of disease extent of various malignant tumors, including malignant lymphoma, but there have been no reports describing the usefulness of FDG-PET imaging in PAL. Here we report a case of PAL that relapsed after chemotherapy and was successfully treated by radiotherapy. FDG-PET imaging revealed that the tumor was localized to a soft-tissue attenuation mass behind the CP cavity in the right thorax, but did not infiltrate the CP cavity. A total dose of 40 Gy was administered to the area that included the PET-positive lesion, instead of including the entire CP cavity in the radiation field. Although computed tomography (CT) showed a residual mass, no FDG uptake was indicated by FDG-PET imaging performed just after the end of radiotherapy, and additional irradiation was not performed. No sign of relapse was found by FDG-PET imaging 3 months later. FDG-PET imaging was useful for both the planning of radiotherapy and assessing the treatment response of PAL.

Enhanced Expression of Neuron‐specific Enolase (NSE) in Pyothorax‐associated Lymphoma (PAL)

Pyothorax‐associated lymphoma (PAL) is a B‐cell lymphoma of mostly large cell type developing in the pleural cavity of patients with long‐standing pyothorax. Neuron‐specific enolase (NSE) is an enolase comprising γ subunit and is located at high levels in neuronal and neuroendocrine cells, together with their neoplasias. Expression of NSE at protein and mRNA levels was examined in PAL and other types (non‐PAL) of non‐Hodgkin's lymphomas. In PAL, serum levels of NSE were elevated (5.32 to 168.0, mean 42.6 ng/ml) and tended to decrease after incisional biopsy followed by chemotherapy (2.38 to 195.5, mean 34.1 ng/ml). Two cell lines established from two cases of PAL produced and secreted NSE in the culture medium. Immunohistochemistry revealed that the positive rate for NSE staining in PAL (10 of 14 cases, 71.4%) was significantly higher than that in non‐PAL cases (6 of 38 cases, 15.8%) (P<0.01). RT‐PCR analysis showed that the expression levels of NSE mRNA in two cell lines and a biopsy sample from PAL were rather similar to those of the control samples from non‐neoplastic lymph nodes. These findings suggest the posttranscriptional regulation of NSE in PAL. Thus, an elevation of serum NSE level in patients with chronic pyothorax may be an indicator of PAL development.

膿胸関連リンパ腫の１手術例

症例は65歳男性.46年前に左結核性胸膜炎の既往がある.左側胸部痛・発熱・咳嗽を主訴に受診した.左側胸部に7×5cmの腫脹と圧痛を認め, 胸部CTにて左胸壁の陳旧性膿胸腔と, 第8肋骨を破壊し外側に突出する3×4cmの腫瘤が存在した.経皮生検にて悪性リンパ腫と診断された.胸壁腫瘍と膿胸嚢の完全摘除術を施行し, 肺は温存した.摘出標本は膿胸腔に接するB細胞型の悪性リンパ腫で, EBV-DNAサザンプロットでEBV感染細胞のoligoclonalな増殖を認めた.EBV-in situ hybridizationにてEBV-encoded small RNAs陽性であり, 膿胸関連リンパ腫 (pyothoraxassociatedlymphoma) と考えた.EBV-LMPとEBV-EBNA2は陰性であった.術後CHOP療法を追加し, 術後10ヶ月現在再発なく健在である.

Expression profile of human herpesvirus 8 (HHV-8) in pyothorax associated lymphoma and in effusion lymphoma

Aims—Pyothorax associated lymphoma (PAL) occurs in a clinical setting of longstanding pyothorax or chronic inflammation of the pleura. Like primary effusion lymphoma, it has an association with Epstein-Barr virus (EBV),...

Sequences of cytotoxic T-lymphocyte epitopes in the Epstein-Barr virus (EBV) nuclear antigen-3B gene in a Japanese population with or without EBV-positive lymphoid malignancies.

Latent infection antigens of EBV, including EBV nuclear antigens (EBNAs) and latent membrane proteins, are expressed in latently infected and immortalized B cells but work as target antigens for host cytotoxic T-lymphocyte (CTL) responses in an HLA class I-restricted manner. Among these latent antigens, the immunodominant CTL epitopes in EBNA3B (EBNA3B 399-408 and EBNA3B 416-424) are well characterized. Mutations and strain differences in these sequences, compared to the prototype A sequence, reduce CTL responses to latently infected B cells. These EBNA3B CTL epitopes in the normal Japanese population and in 2 lymphoid neoplasias, pyothorax-associated lymphoma (PAL) and nasal natural killer-cell lymphoma, were directly sequenced by PCR. Most EBV in peripheral blood leukocytes (PBLs) from healthy Japanese donors exhibited the prototype A sequence, with mutations in approximately 20% (3/16). The sequence of EBNA3B CTL epitopes in lymphoma tissue was obtained in 6 PAL cases, and 5 exhibited mutations or strain differences compared to the prototype A sequence. Furthermore, the EBNA3B sequence in PAL tissue was different from that in PBLs of the same patient or 1 of the sequences found in PBLs. However, the EBNA3B gene in nasal lymphoma tissues exhibited predominantly the prototype A sequence. Because PAL cells expressed EBNA3B mRNA, detected by RT-PCR, but nasal lymphoma cells did not, mutations and strain differences of the sequences of EBNA3B CTL epitopes were specific findings in EBNA3B-positive lymphomas.

Pyothorax-associated lymphoma: relationship with Epstein-Barr virus, human herpes virus-8 and body cavity-based high grade lymphomas

Pyothorax-associated lymphoma (PAL) is a newly-described entity developing several decades after artificial pneumothorax treatment for pulmonary or pleural tuberculosis. It is known to be associated with Epstein-Barr virus (EBV) with constant expression of the two latent membrane proteins: latent membrane protein (LMP)-1 and EBV-associated nuclear antigen (EBNA)-2. We are reporting three new cases of PAL. All of the tumours were of B-cell lineage and classified as large-cell diffuse lymphomas according to the International Working Formulation for the Classification of Lymphomas. The EBV genome was detected in two of the cases with LMP-1 and EBNA-2 expression. No EBV could be detected in the third case suggesting that different mechanisms may be involved in the pathogenesis of the disease. Body cavity-based high grade lymphomas (BCBL) represent a new disease, developing mainly in human immunodeficiency virus (HIV) infected patients: the tumoural cells often contain both human herpes virus (HHV)-8 (or Kaposi's sarcoma herpes virus) and EBV genomes, suggesting that these viruses might co-operate in the pathogenesis of the disease. The pleural location and the association of EBV have led to speculation that PAL could also be related to HHV-8 infection. However, no HHV-8 genome could be detected in any of the 14 tested cases already reported in the literature nor in the two cases we studied (one EBV-positive and one EBV-negative), suggesting that PAL and BCBL are two different entities.

節外性リンパ腫の臨床病理学的な特徴 慢性炎症を基盤に発症するリンパ腫を中心にして

Accumulating evidences suggest that some of extranodal malignant lymphomas develop in the sites of chronic inflammation. In this review, we describe the results of our study on the extranodal lymphomas developing from chronic inflammation, including pyothoraxassociated lymphoma (PAL), and lymphoma of thyroid gland, salivary gland, and gastrointestinal tract. PAL had developed over 20 years history of chronic (tuberculous) pyothorax. Histologically, all were non-Hodgkin's lymphoma with diffuse large cell type being the most common. Immunologic and immunohistochemical studies revealed that PAL have immunophenotype of exclusively B-cell. Epstein-Barr virus (EBV) genome was detected in the lymphoma cells in all PAL cases, which suggested the etiological role of EBV for the development of PAL. We established two cell line from two PAL cases (OPL-1, 2), in which monoclonal latent infection of EBV was identified. We characterized the profile of expression of EBV latent genes and cytokine including interleukin (IL)-6, and IL-10. To investigate the escape mechanism of latent gene expressing PAL cells from host immune surveillance, HLA-A allotype of patients and mutation of EBNA-4 gene were examined. The results suggested that mutation of EBNA-4 gene play a role for PAL development. Thyroid lymphoma and salivary gland lymphoma are closely associated with Hashimoto's disease and Sjogren's syndrome, respectively, known as autoimmune diseases. Our epidemiological study revealed the relative risk for the development of thyroid lymphoma in patients with Hashimoto's disease was 80 times higher than that in general population. Both type of lymphomas showed a female preponderance. The frequencies of lymphoma showing proliferation of small lympoid cells with irregular nucleus and relatively rich cytoplasm, so-called centrocyte-like cells, were relatively high in both type of lymphomas. This type of lymphoma is termed by Isaacson as low-grade lymphoma of mucosa-associated lymphoid tissue (MALT). The frequencies of low grade MALT lymphma in stomach, small intestine, and rectum is 47%, 0%, and 42%, respectively, in our series. Low- grade MALT lymphoma was closely associated with reactive lymphoid hyperplasia in the gastrointestinal tract. Clinicopathologic findings together with EBV status in nasal lymphoma were summarized. Our epidemiological study revealed the clustering of patients with polymorphic reticulosis, a type of nasal lymphoma and constitute lethal midline granuloma syndrome, in the East Asian countries including Japan, Korea, and China.

Pyothorax-associated lymphoma: Description of the first two cases detected in Italy

Pyothorax-associated lymphoma (PAL) is a rare, but distinct, clinico-pathologic entity which occurs most often in Japanese people; to the best of our knowledge, only six cases of it have been reported in Western countries. The tumour develops several decades following artificial pneumothorax or chronic pleuritis due to tuberculous infection, produces pleural effusion associated with extensive local lymphomatous infiltrates, and is sustained by a polymorphic large B-cell clonal proliferation showing EBV integration in the genoma of the neoplastic cells. Herein we describe two cases of PAL observed in Italian patients, both extensively studied on the clinical, pathological, phenotypic, virological, and molecular levels. The two cases occurred, respectively, 45 and 50 years after therapeutic pneumothorax because of tuberculous pleuritis and were characterized by a pleural mass extending to the thoracic wall, which on histological examination were seen to consist of large elements with immunoblastic morphology. Immunohistochemistry show monotypic restriction of Ig light chains, as well as the expression of CD45, B-cell markers (CD20, CD79a, CD45RA), bcl-2 oncogene product, EBNA-2 and, partially, LMP-1. The ratio of cycling cells was extremely high as was the number of mitotic figures. In situ hybridization displayed the presence in the neoplastic cells of the EBV-related small RNAs EBER 1 and 2, which in turn, along with the positivity for EBNA-2 and LMP-1, further strengthened the close relationships between PAL and latent viral infection. Molecular studies revealed, on one hand, clonal rearrangement of the Ig heavy chain J region genes, and on the other, negativity for HHV8 in one case and positivity in the other. These cases of PAL are the first to be documented in Italy; they serve to direct attention to the fact that this condition is not confined to Japanese people, and that its occurrence in Western countries might be underestimated.

Expression of Epstein-Barr virus latent infection genes and oncogenes in lymphoma cell lines derived from pyothorax-associated lymphoma.

Malignant lymphomas frequently develop in the pleural cavity of patients with long-standing pyothorax. The term pyothorax-associated lymphoma (PAL) has been proposed for this type of tumor. Most PALs are diffuse lymphomas of the B-cell type and contain Epstein-Barr virus (EBV) DNA. We have established 2 lymphoma cell lines from biopsy specimens of PAL cases, OPL-1 and OPL-2, and examined their growth characteristics and the expression of EBV latent infection genes and oncogenes. OPL-2 exhibited a more rapid growth and higher saturation density than OPL-1, and only OPL-2 exhibited colony-forming activity in soft agar. OPL-1 and -2 were positive for B-cell differentiation markers and showed clonal surface immunoglobulins. Both line contained a single predominant form of episomal EBV DNA, indicating clonal cellular proliferation of an EBV-infected progenitor cell. OPL-1 and -2 contained type B and A EBV genome, respectively. Expression of EBV nuclear antigen (EBNA)2 mRNA and protein was detected by Northern and Western blot analysis in OPL-1, but not in OPL-2. On the other hand, the expression of latent membrane protein (LMP)1 mRNA in both OPL-1 and -2 was extremely weak and detectable only by reverse transcription-polymerase chain reaction. Protein expression of LMP1 was not observed by Western blot analysis or immunocytochemistry. Both lines expressed c-myc mRNA. Only OPL-1 expressed mRNA of c-fgr, an oncogene whose expression is upregulated by EBNA2. Both OPLs expressed bcl-2 mRNA without detectable expression of LMP1 protein.

Pyothorax-associated lymphoma.

In 1987, we reported three patients with pleural lymphoma developed after a 22-30 year history of pyothorax resulting from artificial pneumothorax for the treatment of pulmonary tuberculosis or tuberculous pleuritis. Based on the pathologic and epidemiologic studies, we regarded the chronic pyothorax (CP) to be etiologically important in the development of pleural lymphoma. Through a nation-wide study in Japan, 37 cases of pleural lymphoma were collected. Pleural lymphoma had developed during the 20 year history of CP in all patients. Histologically all were non-Hodgkin's lymphoma with the diffuse large cell type being the most common. Immunologic and immunohistochemical studies revealed that 32 out of 33 cases were of B-cell lymphoma. From these findings, we proposed the term pyothorax-associated lymphoma (PAL). We examined the presence of Epstein-Barr virus (EBV) genome on the paraffin-embedded specimens in 34 PAL cases and 16 cases of CP alone. Combined polymerase chain reaction (PCR), in situ hybridization, and immunohistochemistry revealed that the EBV genome was detected in lymphoma cells in all PAL, but only one of the cases with CP alone. These findings suggested the etiological role of EBV for the development of PAL. We also described here the character of cell lines established from PAL, association of PAL with Kaposi's sarcoma-associated herpes virus, results of a case-control study on risk factors for development of PAL, and p53 mutations.