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Simple Summary Classic Hodgkin lymphoma (CHL) is a well-defined lymphoid neoplasm with a minority of characteristic neoplastic cells of B cell origin, namely Hodgkin and Reed-Sternberg cells immersed in a rich reactive inflammatory infiltrate in the background. Although CHL has always been set apart from non-Hodgkin lymphomas, cases with morphological and phenotypic features intermediate between CHL and other lymphomas have been described. Whereas some of these lymphomas only represent morphological mimics, others exhibit mutational and gene expression profiles which overlap with CHL, indicating that these cases, frequently termed grey zone lymphomas, reside on the biological boundary between CHL and large B-cell lymphomas. In the present review, we aim to describe the current knowledge of these rare lymphomas, address diagnostic issues and summarize today's concepts on the classification of grey zone lymphomas and related tumors. Classic Hodgkin lymphoma (CHL) is a well-defined neoplasm characterized by the presence of a minority of pathognomonic Hodgkin and Reed-Sternberg (HRS) cells in a reactive inflammatory background. Although genotypically of B cell origin, HRS cells exhibit a downregulated B cell program and therefore are set apart from other B cell lymphomas in the current WHO classification. However, cases with morphological and phenotypic features overlapping with CHL have been recognized, and the category of B cell lymphoma-unclassifiable-with features intermediate between diffuse large B cell lymphoma (DLBCL) and CHL, also termed grey zone lymphoma, was first introduced into the WHO classification in 2008 as provisional entity. These cases, as well as others raising a differential diagnosis of CHL can present diagnostic problems, as well as therapeutic challenges. Whereas some of these lymphomas only represent biologically unrelated morphological mimics, others, especially mediastinal grey zone lymphoma, exhibit genetic and gene expression profiles which overlap with CHL, indicating a true biological relationship. In this review, we address areas of diagnostic difficulties between CHL and other lymphoma subtypes, discuss the biological basis of true grey zone lymphoma based on recent molecular studies and delineate current concepts for the classification of these rare tumors.

Background The upregulated expression of the JAK/STAT pathway promotes tumor growth in Hodgkin lymphoma (HL) and primary mediastinal large B-cell lymphoma (PMBCL). Based on the hypothesis that JAK2 is a therapeutic target, we performed a prospective pilot study using ruxolitinib. Methods Relapsed or refractory patients with HL or PMBCL were eligible for this study, and JAK2 amplification was assessed by fluorescence in situ hybridization. Ruxolitinib was administered orally at a dose of 20 mg twice daily for a 28-day cycle. Treatment was continued for up to 16 cycles or until progressive disease or intolerability. The primary objective was to assess the overall disease control rate comprising complete response (CR), partial response (PR), or stable disease (SD). Results We analyzed 13 HL patients and six PMBCL patients. All responders (one CR, five PR, and one SD) had HL whereas all cases of PMBCL progressed after first or second cycle. The disease control rate for HL was 54% (7/13) with median response duration of 5.6 months. JAK2 amplification was present in six of nine patients tested (four HL, two PMBCL), and three of these HL patients showed PR (n = 2) or SD (n = 1). None of the three HL patients shown to not have JAK2 amplification responded to ruxolitinib. Most treatment-related adverse events were grade 1 or 2 and manageable. Conclusions Ruxolitinib has single-agent activity against HL but does not act against PMBCL with or without JAK2 amplification. Trial registration The study population was patients who had relapsed or refractory HL or PMBCL, and patients were registered for our pilot study after providing written informed consent between November 2013 and November 2015 (CilinicalTrials.gov: NCT01965119).

Primary mediastinal large B-cell lymphoma (PMBL) is a mature large B-cell lymphoma of putative thymic B-cell origin involving the mediastinum with younger age distribution and better prognosis than diffuse large B-cell lymphoma (DLBCL), not otherwise specified. Recently, based on gene expression profile analysis and morphologic findings, cases of PMBL without mediastinal involvement have been reported. In this study, we analyzed 3 cases of nodal DLBCL with morphologic features of PMBL presenting in submandibular or supraclavicular lymph nodes, in middle-aged to elderly patients, 2 of them without clinical or radiologic evidence of mediastinal involvement. The 3 patients presented with stage I/II disease and had excellent response to R-CHOP/R-EPOCH therapy. The 3 cases showed MAL expression and were positive for CD23 and/or CD30. All 3 cases expressed cyclin D1 with copy number gains of CCND1 gene but without rearrangement. There was no rearrangement of CIITA or PDL1/PDL2. Reverse transcriptase-multiplex ligation-dependent probe amplification, a mRNA-based gene expression profile analysis revealed high probability of PMBL (87.6%, 98.7%, and 99%) in these 3 cases. Targeted next-generation sequencing analysis showed SOCS1 mutations in the 3 cases, and TNFAIP3 and XPO1 mutations in one, further supporting the diagnosis of PMBL. In conclusion, we report 3 cases of nodal PMBL, 2 of them without mediastinal mass, and expression of cyclin D1 due to copy number gains of CCND1 gene, a diagnostic pitfall with mantle cell lymphoma and DLBCL, not otherwise specified.

Objectives We aimed at investigating the relationship between classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBL), and gray zone lymphoma (GZL) with intermediate characteristics between cHL and PMBL, from the perspective of the aberration in programed cell death 1 and the programed death ligands (PDLs) network. Methods We explored the expression levels of PDLs and chromosomal anomalies in 67 cases: 34 cases with cHL, 20 with PMBL, and 13 with GZL, using immunohistochemical analyses and Fluorescence In Situ Hybridization (FISH). Results Twenty-one cHL (62%), 3 PMBL (15%), and 6 GZL (46%) cases showed staining to PD-L1 antibodies in more than 70% of tumor cells. Two cHL (6%), 10 PMBL (50%), and 3 GZL (23%) cases were not stained by PD-L1 antibodies. Patients over 40 years old manifest more frequent expression of PD-L1 in cHL. Proportion of tumors stained by PD-L2 antibody was increased in PMBL. FISH analyses with a PD-L1/PD-L2 probe detected 5 amplification, 1 gain, and 7 polysomy cases in cHL, 1 amplification and 1 polysomy case in GZL, and amplification in 1 PMBL case. Conclusion We identified increased staining of PD-L1 in cHL and that of PD-L2 in PMBL. GZL had a pattern similar to that of cHL.

AIM We describe the clinical, histopathological and immunophenotypic characteristics of an HIV-infected adult man on antiretroviral therapy who presented with an EBV-positive grey zone lymphoma. CASE PRESENTATION A 56-year-old HIV infected man from Uganda presented with a four month history of progressive abdominal swelling and B-symptoms. He was on highly active antiretroviral therapy (HAART) and cotrimoxazole. He was afebrile (36.9°C), severely wasted (BMI 14.8), and mildly anaemic. On physical examination, he had a 15 by 8 cm mass in the hypogastrium and umbilical region. The total white cell count was 8.3×103/μL; neutrophils, 5.72×103/μL; haemoglobin 11.1g/dL, platelets 528×103/μL, LDH 197 IU/L and CD4 367/μL. Abdominal ultrasound and CT scan showed a tumour involving the mesentery, jejunum and mid ileum. At laparotomy, a biopsy was taken, fixed, processed and stained with Haematoxylin & Eosin (H & E). Histopathology demonstrated large pleomorphic cells admixed with inflammatory smaller cells, Reed-Sternberg-like cell variants and frequent abnormal mitoses. Biomarkers CD20, PAX5, CD30 were positive but ALK negative (immunohistochemistry and strong EBER positivity in situ hybridization. The patient improved on modified CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) therapy. DISCUSSION The tumour had features intermediate between mediastinal large B cell lymphoma and classical Hodgkin lymphoma. CONCLUSION We present a case of EBV-positive grey zone lymphoma in an HIV-infected man on HAART therapy diagnosed and treated in a resource constrained medical setting. The histological features are unusual and represent a low incidence lymphoma that is recognized by mixed features reminiscent of Hodgkin's lymphoma and mediastinal large B-cell lymphoma.

Purpose: Classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (MLBCL) share similar histologic, clinical, and genetic features. In recent studies, we found that disease-specific chromosome 9p24.1/JAK2 amplification increased JAK2 expression and activity in both cHL and MLBCL. This prompted us to assess the activity of a clinical grade JAK2 selective inhibitor, fedratinib (SAR302503/TG101348), in in vitro and in vivo model systems of cHL and MLBCL with defined JAK2 copy numbers. Experimental Design: We used functional and immunohistochemical analyses to investigate the preclinical activity of fedratinib and associated biomarkers in cell lines and murine xenograft models of cHL and MLBCL with known 9p24.1/JAK2 copy number. Results: Chemical JAK2 inhibition decreased the cellular proliferation of cHL and MLBCL cell lines and induced their apoptosis. There was an inverse correlation between 9p24.1/JAK2 copy number and the EC50 of fedratinib. Chemical JAK2 inhibition decreased phosphorylation of JAK2, STAT1, STAT3, and STAT6 and reduced the expression of additional downstream targets, including PD-L1, in a copy number–dependent manner. In murine xenograft models of cHL and MLBCL with 9p24.1/JAK2 amplification, chemical JAK2 inhibition significantly decreased JAK2/STAT signaling and tumor growth and prolonged survival. In in vitro and in vivo studies, pSTAT3 was an excellent biomarker of baseline JAK2 activity and the efficacy of chemical JAK2 inhibition. Conclusions: In in vitro and in vivo analyses, cHL and MLBCL with 9p24.1/JAK2 copy gain are sensitive to chemical JAK2 inhibition suggesting that clinical evaluation of JAK2 blockade is warranted. Clin Cancer Res; 20(10); 2674–83. ©2014 AACR.

Mediastinal large B-cell lymphoma (MLBL) represents 2% of mature B-cell non-Hodgkin lymphoma in patients ≤ 18 years of age. We analyzed data from childhood and adolescent patients with stage III MLBL (n = 42) and non-MLBL DLBCL (n = 69) treated with Group B therapy in the French-American-British/Lymphome Malins de Burkitt (FAB/LMB) 96 study. MLBL patients had a male/female 26/16; median age, 15.7 years (range, 12.5-19.7); and LDH < 2 versus ≥ 2 × the upper limit of normal, 23:19. Six MLBL patients (14%) had < a 20% response to initial COP (cyclophosphamide, vincristine, and prednisone) therapy. Central pathology revealed approximately 50% with classical features of primary MLBL. Five-year event-free survival for the stage III MLBL and non-MLBL DLBCL groups was 66% (95% confidence interval [CI], 49%-78%) and 85% (95% CI, 71%-92%), respectively (P < .001; 14%). The 5-year overall survival in the 42 MLBL patients was 73% (95% CI, 56%-84%). We conclude that MLBL in adolescent patients is associated with significantly inferior event-free survival compared with stage III non-MLBL DLBCL and can be of multiple histologies. Alternate treatment strategies should be investigated in the future taking into account both adult MLBL approaches and more recent biologic findings in adult MLBL.

Primary mediastinal (thymic) large B-cell lymphoma (PMLBCL) and nodular sclerosing classical Hodgkin lymphoma (NSCHL) are the major histological types of lymphoma affecting the mediastinum. We reviewed 27 patients with PMLBCL and 14 patients with NSCHL. A poor performance status, high serum lactate dehydrogenase level and strong positivity for PAX5 were all significantly more common in patients with PMLBCL than in those with NSCHL. Severe fibrosis was frequent in NSCHL, but not in PMLBCL. PDL1 was expressed by 11/25 PMLBCLs (44.0%) vs. 1/9 NSCHLs (11.1%). Expression of BCL6 was significantly more frequent in PDL1-positive PMLBCL than in PDL1-negative PMLBCL, but there were no clinical differences between these two groups. Two patients with PMLBCL with a poor prognosis had CD20(-), CD79a(+), CD15(-), and CD30(-), possibly representing a subtype of mediastinal gray zone lymphoma.

The addition of rituximab to cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) improved the outcome of patients with diffuse large B-cell lymphoma (DLBCL). However, the impact of rituximab (R-CHOP) is still not determined in primary mediastinal large B-cell lymphoma (PMBCL), a subtype of DLBCL, especially in Asian patients. Thus, we analyzed the treatment outcome of PMBCL patients (n = 21) treated with R-CHOP and compared it with the historical group treated with CHOP (n = 14). The rate of complete response for R-CHOP was higher than that of CHOP (17/21, 81.0% vs. 8/14, 57.2%), although the difference was not statistically significant (P = 0.151). The number of patients with disease progression or relapse was higher in the CHOP group (6/14, 42.9%) than the R-CHOP group (2/21, 9.5%). Thus, patients treated with R-CHOP had higher 2-year progression-free survival (79.0%) than those treated with CHOP (50.0%, P = 0.043). Although the 2-year overall survival of the R-CHOP was also superior to that of the CHOP group (82.7% vs. 57.1%), this survival benefit did not reach statistical significance (P = 0.081). In conclusion, our comparison suggests that R-CHOP may increase response and reduce relapse resulting in prolongation of progression-free survival of patients with PMBCL.

目的: 縦隔大細胞型 B 細胞性悪性リンパ腫 (mediastinal large B-cell lymphoma: 以下, MLBL) の細胞学的特徴を明らかにする.方法: 過去 10 年間, 福岡大学病理学教室にて, 組織学的に MLBL と診断された 11 例について臨床像, 捺印標本の細胞像〔Papanicolaou (以下, Pap 染色, Giemsa 染色) 〕, 免疫組織的特徴を検討した.成績: (1)細胞診上, 腫瘍細胞の出現パターンをびまん型, 集簇型, 散在型の 3 つに分類した. びまん型は, 大型のリンパ球様細胞が敷き石状, 単調な腫瘍細胞の出現をみる. 集簇型では, 腫瘍細胞は重積性を示す細胞集塊として出現し, 核は大型の円形∼楕円形で, クロマチンは粗大顆粒状, 細胞質が泡沫状を呈する. 散在型では, 細胞数は少なく, 大型核を有する腫瘍細胞が散在性に認められ, 多核例もみる. (2)免疫組織染色では, CD23: 5 例, CD10: 3 例, Bcl-2: 8 例, Bcl-6: 9 例, MUM-1: 8 例, CD30: 8 例陽性であった. Bcl-2, Bcl-6 領域の probe を使い DNA Fluorescence in situ hybridization (FISH) 法で染色体転座の有無を調べたが, 全例で陰性であった. Epstein Barr virus encoded RNA (EBERs) を同定する ISH 法では, 全例感染を認めなかった.結論: MLBL は細胞学的に 3 型に分けられた. 集簇型例は悪性上皮性腫瘍と鑑別が困難であった. 縦隔腫瘍では, 上皮細胞様にみえる悪性リンパ腫があることを念頭に置き, 細胞診断する必要があると考えた. 散在型では, ホジキンリンパ腫に類似の細胞浸潤像を呈した.

Mediastinal B-cell lymphoma is a locally highly aggressive tumour which was first described in the early 1980s. The incidence is about 2-3% of all non-Hodgkin's lymphomas. The conceptional evolution of this lymphoma entity was hampered by its low incidence and the broad spectrum of morphological variants present. However, since mediastinal B-cell lymphoma has distinct morphological, immunological, genetic, and clinical features, it has been listed in the revised European-American Classification of Lymphoid Neoplasms (REAL-Classification) since 1994 as a variant of diffuse large B-cell lymphoma. In the World Health Organization classification of malignant lymphomas, mediastinal B-cell lymphoma is now listed with an own disease code (ICD-9679/3).

A 32-year-old female underwent laparoscopic salpingectomy of an ectopic (third) pregnancy under general anaesthesia, at approximately six weeks' amenorrhoea. She developed severe respiratory distress after extubation and died on the second postoperative day. It appears that she had a history of a mild, persistent productive cough for a period of about a month prior to the operation that was attributed to an upper respiratory tract infection. Autopsy demonstrated the presence of a large mediastinal tumour, whose existence was apparently unsuspected preoperatively, encasing the ascending thoracic aorta, aortic arch and the proximal segments of the brachiocephalic and subclavian arteries, and causing extrinsic airway compression. Subsequent microscopic examination showed histological and immunohistochemical features of a mediastinal large B-cell lymphoma. It is thought that the mechanical effects exerted by the advanced mediastinal tumour upon the airways and the thoracic cage, coupled with the pathophysiological effects of general anaesthesia on respiratory movement and airway patency, had led to the patient's unfortunate demise in early pregnancy.

In recent years, overlap in biologic and morphologic features has been identified between classic Hodgkin lymphoma (cHL) and B-cell non-Hodgkin lymphoma. Nevertheless, the therapeutic approaches for these diseases remain different. We undertook a study of "mediastinal gray zone lymphomas" (MGZL), with features transitional between cHL nodular sclerosis (NS) and primary mediastinal large B-cell lymphoma (MLBCL) to better understand the morphologic and immunophenotypic spectrum of such cases. Twenty-one MGZL cases were identified over a 20-year period. We also studied 6 cases of composite or synchronous lymphoma with two distinct components at the same time (cHL-NS and MLBCL) and 9 sequential cases with MLBCL and cHL-NS at different times. All patients had a large mediastinal mass. Immunohistochemical studies focused on markers known to discriminate between cHL and MLBCL, including B-cell transcription factors. VJ-PCR was performed in 8 cases to look at clonality of the immunoglobulin heavy chain gene (IgH). Of the gray zone cases, 11 had morphology reminiscent of cHL-NS, but with unusual features, including a large number of mononuclear variants, diminished inflammatory background, absence of classic Hodgkin phenotype, and strong CD20 expression (11 of 11). Ten cases had morphology of MLBCL, but with admixed Hodgkin/Reed-Sternberg and lacunar cells, absent (3 of 10) or weak (7 of 10) CD20 expression, and positivity for CD15 in 7 cases. B-cell transcription factor expression in the gray zone cases more closely resembled MLBCL than cHL with expression of Pax5, Oct2, and BOB.1 in all but 1 case studied (14 of 15). MAL staining was found in 7 of 10 MGZL, and in at least one component of 6 of 7 evaluable composite or sequential MLBCL/cHL cases. Two cases of sequential lymphoma showed rearrangements of the IgH gene of identical size: one in which MLBCL was the first diagnosis and one in which MLBCL was diagnosed at relapse, indicating clonal identity for the two components of cHL and MLBCL. There is accumulating evidence that MLBCL and cHL are related entities. Further support for a relationship between MLBCL and cHL-NS is provided by composite and metachronous lymphomas in the same patient, as well as the existence of MGZL with transitional morphology and phenotype.

Mediastinal large B-cell lymphoma (MLBCL) is a recently identified subtype of diffuse large B-cell lymphoma (DLBCL) that characteristically presents as localized tumors in young female patients. Although MLBCL has distinctive pathologic features, it clinically resembles the nodular sclerosis subtype of classical Hodgkin lymphoma (cHL). To elucidate the molecular features of MLBCL, we compared the gene expression profiles of newly diagnosed MLBCL and DLBCL and developed a classifier of these diseases. MLBCLs had low levels of expression of multiple components of the B-cell receptor signaling cascade, a profile resembling that of Reed-Sternberg cells of cHL. Like cHLs, MLBCLs also had high levels of expression of the interleukin-13 (IL-13) receptor and downstream effectors of IL-13 signaling (Janus kinase-2 [JAK2] and signal transducer and activator of transcription-1 [STAT1]), tumor necrosis factor (TNF) family members, and TNF receptor-associated factor-1 (TRAF1). Increased expression of STAT1 and TRAF1 in MLBCL was confirmed by immunohistochemistry. Given the TRAF1 expression and known link to nuclear factor-kappa B (NF- kappa B), MLBCLs were also evaluated for nuclear translocation of c-REL protein. In almost all cases, c-REL was localized to the nucleus, consistent with activation of the NF-kappa B pathway. These studies identify a molecular link between MLBCL and cHL and a shared survival pathway.

Extramedullary myeloid cell tumour (EMMT) localised to the mediastinum is a rare manifestation of acute myeloid leukaemia, forming less than 4% of all cases of EMMT. In contrast to other types of EMMT, cytogenetic characteristics of this rare entity are relatively unknown. This report describes a patient with EMMT who had evidence of superior vena cava syndrome and normal peripheral blood counts at diagnosis. The results from an initial biopsy specimen were consistent with a diagnosis of mediastinal large B cell lymphoma. A diagnosis of acute myeloid leukaemia was made three months after initial diagnosis by bone marrow examination. Review of the initial biopsy specimen showed strong positivity for myeloperoxidase, revealing that the patient had been initially misdiagnosed as having large B cell lymphoma. Cytogenetic studies revealed a near triploid and near tetraploid karyotype with structural abnormalities in 12 and three metaphases, respectively. Review of the literature showed that a near tetraploid or triploid karyotype is found in most of the reported cases of mediastinal EMMT. Thus, the presence of a near triploid/tetraploid karyotype and mediastinal EMMT may represent a specific subset of EMMT. The biological relevance of this observation is discussed.

背景:胸水細胞診で診断し得た縦隔原発硬化性大細胞型B細胞リンパ腫 (mediastinal large B-cell lymphoma: 以下MLBL) の1例を経験したので報告する.症例:患者は19歳, 男性で近医にて前縦隔腫瘤, 胸水貯留ならびに血中LDの上昇を指摘され, 当院紹介入院となり, 胸水細胞診と前縦隔腫瘤のCTガイド下生検が施行された. 胸水中には一点を中心として核が平面的に分葉しクローバー状を呈するものや好中球のように糸状核で核が連結されるものなどが認められ, いわゆる“multilobated nuclei”の形態を呈する腫瘍細胞が出現していた. 前縦隔腫瘤の生検組織には多分葉核を示す大型異型細胞がびまん性に増殖し, 膠原線維の増生による硬化像を伴っており, MLBLと診断された.結論:MLBLは核形態と臨床病理学的事項が特徴的であり, 細胞像を詳細に観察し, 臨床所見も考慮すれぼ細胞診に於いても診断可能であると考えられた.

Purpose: Primary mediastinal large B-cell lymphoma (PML) has clinicopathologic features distinct from those of other diffuse large-cell lymphomas. However, the optimal treatment for this tumor is evolving, and in particular, the role of radiation therapy remains undefined. We conducted a retrospective review to evaluate the role of radiation therapy in this disease. Methods and Materials: The medical records of 40 consecutive patients with Ann Arbor Stage I or II PML treated at our institution from January 1980 to December 1995 were reviewed. There were 18 patients with Stage I disease and 22 patients with Stage II disease; 62.5% were women and 37.5% were men. The median age was 32.4 years (range, 17–74 years). The tumor scores were 0 in 1 patient, I in 5 patients, II in 13 patients, III in 7 patients, IV in 4 patients, and unknown in 10 patients. The International Prognostic Index (IPI) was 0 in 10 patients, I in 26 patients, II in 2 patients, and unknown in 2 patients. All patients were treated with doxorubicin-based chemotherapy, and 35 patients received radiation therapy. For most patients who received radiation therapy, an involved field or a modified-mantle field was used, and a dose of 40 Gy in 20 fractions or 39.6 Gy in 22 fractions was administered. Univariate analysis was performed to identify prognostic factors. Results: The median follow-up in surviving patients was 56 months (range, 19–194 months). The actuarial 5-year relapse-free survival (RFS) rate and overall survival (OS) rate for all patients were 67% and 72%, respectively. Thirty-five patients achieved a complete response; 32 of these patients received radiation therapy. The patterns of failure for the complete responders were as follows: locoregional failure alone for 1 patient (at the margin of the radiation field); distant failure alone for 5 patients; and both locoregional (in-field) and distant failure for 1 patient. There were no failures after 2.5 years. None of the 5 patients who never achieved a complete response had local control, and all died with disease. Only 2 of the 5 completed the planned course of radiation therapy; both had massive mediastinal disease. There was no treatment-related death from the initial chemotherapy or radiation therapy. One patient developed a second malignancy (sarcoma) within the radiation field after 13 years. The tumor score was a significant predictor of RFS ( p = 0.016) and OS ( p = 0.006), but the IPI did not prove to be a significant predictor. Conclusion: We recommend consolidative radiation therapy in view of the excellent local control and the lack of significant toxicity. Modified mantle or involved field appears to be an adequate volume, and 39.6–40 Gy appears to be an adequate dose. The tumor score is a significant prognostic factor.

Summary There are few reports of unmanipulated HLA-haploidentical nonmyeloablative stem cell transplantation (NST) using only pharmacological acute graft-vs.-host disease (GVHD) prophylaxis. We present here a successful case of unmanipulated HLA-haploidentical NST for mediastinal large B cell lymphoma that was resistant to autologous peripheral blood stem cell transplantation (PBSCT). The conditioning regimen consisted of fludarabine, busulfan and rabbit anti-T-lymphocyte globulin (ATG) in addition to rituximab. GVHD prophylaxis was performed using tacrolimus and methylprednisolone 1 mg/kg. The patient had rapid engraftment, with 100% donor chimaerism in the lineages of both T cells and granulocytes on day +12, but developed no GVHD clinically. The patient is still in complete remission past day +1020, with no sign of chronic GVHD without receiving immunosuppressive agents. HLA-haploidentical NST may be performed without utilizing mixed chimaerism.

Although primary mediastinal large B-cell lymphoma (PMBL) and classic Hodgkin lymphoma of the nodular sclerosis type (CHL-NS) are distinct diseases, they share several clinical characteristics and biologic features. Given that, it is not surprising that there exist mediastinal lymphomas that do not fit well into either category but have clinical and morphologic features overlapping and transitional between PMBL and CHL-NS. The term mediastinal gray zone lymphoma (MGZL) has been used for these tumors, which are included in the World Health Organization classification as “B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma.” Although several studies have evaluated different therapeutic strategies in PMBL and CHL-NS, there is a paucity of prospective experience treating MGZL, given its rarity and relatively recent recognition. Historically, diseases that today would be categorized as MGZL were probably called “anaplastic large-cell lymphoma Hodgkin-like,” and their outcome with standard approaches was poor, with short overall survivals. In this review—following a discussion of the biology and clinical features of MGZL, and how they compare to PMBL and CHL-NS—we outline how the treatment of PMBL and CHL-NS has evolved in recent years, and how we believe MGZL should be approached therapeutically.

The mediastinal large B-cell lymphoma is described as a distinct entity among high-grade non-Hodgkin’s lymphomas. A total of 340 cases representing most likely this particular lymphoma have been descr

Dysregulated JAK2 signaling has been shown to play a significant role in the pathogenesis of myeloproliferative disorders. Recently, our work comparing gene expression signatures of primary mediastinal large B-cell lymphomas (PMLBCL) versus nodal diffuse large B-cell lymphomas (DLBCL) revealed a relative increase in JAK2 transcripts in the former suggesting a role for increased JAK2 signaling in a subset of these tumors. Given the likelihood of increased JAK2 signaling in PMLBCL, we sought to determine whether JAK2 activating mutations were an alternative mechanism for increased JAK2 signaling in untreated PMLBCLs. We performed amplification refractory mutation analysis for the JAK2 (V617F) mutation and bi-directional sequencing for the recently described JAK2 exon 12 mutations on genomic DNA isolated from a well characterized cohort of PMLBCLs. No evidence of the mutant JAK2 (V617F) allele or JAK2 exon 12 mutations was detected in 31 PMLBCL cases tested. Analysis using cell lines derived from PMLBCLs (n=1) and from the molecularly similar classical Hodgkin lymphoma (n=4) also failed to reveal involvement of this mutant JAK2 allele. Taken together, these results suggest that JAK2 signaling in PMLBCLs occurs by mechanisms distinct from JAK2 (V617F) or JAK2 exon 12 activating mutations.

Mediastinal large B-cell lymphomas (MLBCLs) are considered as a subtype of diffuse large B-cell lymphoma; however, they exhibit completely different patterns of dissemination. Since they share a number of surface markers with thymic B cells, a close relationship was assumed. MLBCLs arise extranodally within the anterior mediastinum and have a low propensity to metastasize. To address the preferential positioning of MLBCL, we focused on homeostatic chemokines involved in B-cell compartmental homing in secondary lymphoid organs, which are also capable of shaping lymphoid niches in ectopic sites. Here, we applied immunohistochemistry to assess chemokine receptor and ligand expression in situ. Flow cytometry was used to identify the chemokine receptor profile on an MLBCL-derived cell line, Karpas1106 and on thymic B cells. Migration assays were performed to examine functionality of chemokine receptors. Electrophoretic mobility shift assay was applied to score for NF-κB activity. Using immunohistochemistry, we obtained an unexpectedly low-expression frequency for the chemokine receptors CXCR5 and CCR7 in primary lesions. Although the mature B-cell marker CCR6 was absent in most cases, the lineage aberrant marker CCR9 emerged in the majority of MLBCL cases. Given the role of NF-κB in the transcriptional activation of CCR7, we identified the involvement of the noncanonical activation pathway in MLBCLs. MLBCLs exhibit a diagnostic chemokine receptor profile that is instrumental in the discrimination from diffuse large B-cell lymphoma not otherwise specified and classical Hodgkin lymphoma. Furthermore, we suggest that low-abundance expression of CCR7 and CXCR5 may hinder lymphoma cells from nodal dissemination. © 2009 UICC

Six cases of mediastinal large B-cell lymphoma (MLCL) with sclerosis were analyzed for the presence and patterns of c-myc and bcl-2 loci rearrangements, and for the presence of Epstein-Barr virus DNA sequences by Southern blot hybridization, c-myc gene alterations were found in three of six cases. Two cases showed the presence of mutations or small rearrangements at the 3′ end of the first exon. The c-myc gene abnormalities found in these two cases are similar to those observed in the translocation 8;14 of the endemic Burkitt's lymphomas or in its variants t(2;8) and t(8;22). A third case showed a major rearrangement of c-myc gene, with truncation within its first intron, similar to those observed in sporadic Burkitt's and in acquired immunodeficiency- associated lymphomas. None of the cases displayed bcl-2 gene rearrangements or contained viral sequences. Our data suggest a possible role for a translocation-mediated c-myc activation in the pathogenesis of MLCL. Conversely, bcl-2 gene and Epstein-Barr virus do not appear to be involved in the pathogenesis of these peculiar lymphomas. The association between c-myc structural modifications and MLCL also seems to be of relevance in light of the peculiar tendency of this tumor to involve unusual extranodal site (eg, kidney), reminiscent of the spreading attitude of Burkitt's limphomas.

We report the clinical findings of 21 consecutive patients affected by mediastinal large B-cell lymphoma with sclerosis. This type of lymphoma is a recently described histopathologic entity characterized on clinical grounds by distinctive features, which, according to our series, can be summarized as follows: young age (median, 30 years; range, 15 to 42 years), prevalence of females over males (15 v six), rare occurrence of superficial lymph node enlargement (three of 21 patients), and involvement of unusual extranodal sites (kidney six, adrenal cortex two patients). The clinical course appears to be closely related to treatment. In fact, complete remission (CR) was not obtained in the six patients submitted to conventional cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP plus bleomycin (CHOP-Bleo) regimens until 1985, as opposed to 13 CRs reached in the 15 patients subsequently treated with more aggressive regimens after 1985 (methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin [MACOP-B], 12 patients; methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone [M-BACOD], two patients; and vincristine, cyclophosphamide, fluorouracil, cytarabine, doxorubicin, methotrexate, and prednisone [F-MACHOP], one patient; plus involved-field radiotherapy, 10 patients). Among the 13 patients who achieved a CR, only one relapse was observed at 10 months. The median overall survival of complete responders after an observation period of 11 to 69 months has not yet been reached, and the event-free survival curve indicates that 90% of patients who achieve CR may be potentially cured.

Mediastinal large B-cell (MBL) and classical Hodgkin lymphoma (HL) have several pathogenic mechanisms in common. As we recently observed aberrant tyrosine kinase (TK) activities in HL, we now analysed also MBL for such activities. Indeed, MBL and HL were the only B-cell lymphomas where elevated cellular phospho-tyrosine contents were typical features. Three TKs, JAK2, RON and TIE1, not expressed in normal B cells, were each expressed in about 30% of MBL cases, and 75% of cases expressed at least one of the TKs. Among the intracellular pathways frequently triggered by TKs, the PI3K/AKT pathway was activated in about 40% of MBLs and essential for survival of MBL cell lines, whereas the RAF/mitogen-activated protein kinase pathway seemed to be inhibited. No activating mutations were detected in the three TKs in MBL cell lines and primary cases. RON and TIE1 were each also expressed in about 35% and JAK2 in about 53% of HL cases. JAK2 genomic gains are frequent in MBL and HL but we observed no strict correlation of JAK2 genomic status with JAK2 protein expression. In conclusion, aberrant TK activities are a further shared pathogenic mechanism of MBL and HL and may be interesting targets for therapeutic intervention.

Patients with primary large B-cell lymphomas of the mediastinum (PMBL) who suffer early relapse have a low likelihood of achieving a prolonged second remission with conventional salvage therapy. Here we describe the case of a 33-year-old woman with PMBL refractory to 6 lines of therapy before undergoing salvage therapy with rituximab, ifosfamide and etoposide followed by high-dose therapy, autologous transplantation, and sequential non-myeloablative allogeneic transplantation, who remains in ongoing complete remission for more than 39 months and is apparently cured. The specific roles of the components of the successful salvage therapy are discussed.

To determine the possible role of aberrant somatic hypermutation (ASHM) and activation-induced cytidine deaminase (AID) expression in the pathogenesis of mediastinal large B-cell lymphoma (MBL), the mutational status of genes affected by ASHM, including c-MYC, PAX-5 and RhoH, was analysed, and the expression level of AID mRNA in tumour specimens from six patients with MBL was determined. Mutations in one or more genes and high expression of AID mRNA were detected in all the six cases of MBL. These results suggest that ASHM and AID expression may have a role in the pathogenesis of MBL.

Mediastinal (thymic) large B-cell lymphoma (MBL) has been defined as a subtype of diffuse large B-cell lymphoma (DLBL) arising in the mediastinum with characteristic clinicopathological features. It has been postulated that MBL arise from non-circulating thymic B-cells and represent a distinct lymphoma entity, however, the histogenesis of the disease is not yet fully understood. In order to clarify the histogenetic derivation of MBL and to determine the relationship of MBL to thymic B-cells we have analyzed the nucleic acid sequences of immunoglobulin (Ig) heavy chain variable region (VH) and 5' noncoding region of BCL-6 genes in normal thymic B-cells and six cases of MBL. Thymic B-cells and tumor cells of MBLs displayed hypermutated VH and/or BCL-6 genes but intraclonal divergence did not associate with these mutations. Since somatic mutations of the IgVH and BCL-6 genes are histogenetic markers of B-cell transit through the germinal centre (GC), these results suggest that both thymic B-cells and MBLs derived from GC or an equivalent environment where B-cells underwent somatic hypermutation. The similar pattern of mutations of IgVH and BCL-6 genes found in thymic B-cells and MBLs further supports the theory that MBLs originate from thymic B-cells.

We report on the immunophenotype, clinical findings and response to aggressive chemotherapy of 18 patients with mediastinal large B-cell lymphoma (MLCL). Cases were collected from a series of 286 high-grade non-Hodgkin's lymphomas (HG-NHL) which, in the period September 1988 to August 1991, were enrolled in a prospective multicentre trial designed to compare the MACOP-B and F-MACHOP regimens. Immunostaining on frozen sections revealed a previously unrecognized phenotype, i.e. co-expression of B-cell (CD19, CD20, CD22, Ig-associated dimer) and activation-associated antigens (CD30 and CDw70) in about 60% of MLCL cases; in contrast, the activation-associated antigens CD25 and Ki-27 (unclustered) were consistently negative. This peculiar phenotype may reflect a derivation of the tumour from a subset of thymic activated B cells. Clinically, the patients (median age 31 years; F/M ratio 2.6) presented with bulky mediastinal mass (72%) associated with mediastinal syndrome in > 50% cases; disease was stage IIA in most cases. All 18 patients received aggressive chemotherapy (F-MACHOP 11; MACOP-B 7). Complete response (CR) was achieved in 57.1% of cases treated with MACOP-B. In contrast, the response of the 11 MLCL treated with F-MACHOP was poor (CR 18.2%) as compared to that of the 135 HG-NHL treated with the same regimen during the trial (CR 69.6%). This difference was still statistically significant after adjusting for negative prognostic factors (mediastinal mass > 10 cm plus increased LDH) and suggests that F-MACHOP might not be the most appropriate regimen for this kind of lymphoma.

Abstract 747 Background: Mediastinal gray zone lymphoma (MGZL) is a newly recognized entity demonstrating transitional morphologic and immunophenotypic features between classical Hodgkin's lymphoma, nodular sclerosis subtype (CHLNS) and primary mediastinal large B-cell lymphoma (PMLBCL). CHLNS and PMLBCL differ in morphology, immunophenotype, and therapeutic consequences. MGZLs present a challenge both to the pathologist and clinician, as the criteria to distinguish MGZL from CHLNS and PMLBCL are still imprecise, and the optimal treatment approach is as yet undetermined. Purpose of Study: Epigenetic changes have been implicated in the loss of the B-cell program in CHL, and might provide a basis for the immunophenotypic alterations seen in MGZL. Thus, we performed a large scale DNA methylation array of MGZL, CHLNS, and PMLBCL as well as diffuse large B-cell lymphoma (DLBCL) to investigate the biological underpinnings of MGZL and how it corresponds to the two related entities CHLNS and PMLBCL and the less related entity DLBCL. Microdissection of tumor cells was performed to identify changes in the tumor cell population, and allow comparison with the background inflammatory and stromal milieu. Results: Principal component analysis (PCA) demonstrated that MGZLs have a distinct epigenetic profile intermediate between CHLNS and PMLBCL but clearly different from that of DLBCL. Analysis of common hypo- and hypermethylated CpG targets in MGZL, CHLNS, PMLBCL and DLBCL was performed. MGZL showed great overlap with CHLNS (49 common targets) and PMLBCL (50 common targets). In contrast, MGZL shared only two common targets with DLBCL. However, using the epigenetic profiles we were able to establish class prediction models that could distinguish between MGZL, CHLNS and PMLBCL with a final combined prediction of 100%. Pyrosequencing for selected CpG sites from different genes were performed and confirmed the high accuracy of methylation array results. Conclusions: MGZLs share several clinical and pathological features with CHLNS and PMLBCL. Our findings further underscore the close biological relationship between MGZL, CHLNS and PMLBCL, and ready distinction from DLBCL. However, MGZL has a distinct epigenetic identity that shares elements of both parent disorders. As the first biological study on MGZL, our results provide novel insights into MGZL pathogenesis, and its relationship to CHLNS and PMLBCL. Disclosures: Emmert-Buck: NIH: Michael Emmert-Buck is an inventor on all NIH patents covering laser capture microdissection technology and receives royalty payments through the NIH technology transfer program., Patents & Royalties.

Summary We describe a man with relapsed large B cell mediastinal lymphoma and associated infected large anterior chest wall defect who required high dose salvage therapy for his underlying disease. An initial mediastinotomy wound, associated with recurrent sepsis, had developed into an abscess, then fistula and eventually a large anterior chest wall defect. Safe use of salvage chemotherapy required reconstructive surgery consisting of a pedicled muscle flap. The subsequent high dose chemotherapy was carried out without complications and 15 months later the patient is alive and well.

Background Discordant lymphoma is defined by the simultaneous presence of two or more distinct types of lymphomas at different anatomic sites. With fewer than 20 studies reporting cases of discordant lymphoma to date, the incidence of this condition is believed to be very low. Case Presentation Here, we report a case of discordant lymphoma in a 34-year-old female patient that involved mediastinal large B-cell lymphoma and nodular sclerosis Hodgkin lymphoma in the right supraclavicular lymph nodes. The patient presented with a mass in the mediastinum and enlargement of the right supraclavicular lymph nodes, but no obvious signs of lymphoma. Histological examination revealed that the encapsulated mediastinal mass contained medium- or large-size tumor cells with lightly stained cytoplasm and round vesicular nuclei as well as a high percentage of mitotic cells; strongly positive immunohistochemical staining for PAX5, CD20, and CD79a also was observed. Examination of biopsied right supraclavicular lymph node tissues revealed separation by collagen fibers, extensive inflammatory cell infiltration, and large-size tumor cells, such as Reed–Sternberg cells. These tissues stained strongly positive for PAX5 and CD30, weakly positive for CD15, and negative for Epstein-Barr viral RNA. We also found monoclonal gene rearrangement in the immunoglobulin heavy chain gene in the mediastinal large B-cell lymphoma, but no monoclonal gene rearrangement in the nodular sclerosis Hodgkin lymphoma. These findings suggested that these two lymphomas were not of a common clonal origin. The patient was treated by surgical excision of the mediastinal mass followed by radio-chemotherapy, and no metastasis or recurrence occurred during a follow-up period of 32 months. Conclusion A review of previously reported cases indicated that the clinical manifestations and pathological features of discordant lymphoma are diverse due to variation in the types of lymphomas involved. Physicians must have an awareness of discordant lymphoma to avoid incorrect and missed diagnoses, especially considering that the true incidence may not be as low as previously believed. Electronic supplementary material The online version of this article (doi:10.1186/s13000-015-0450-6) contains supplementary material, which is available to authorized users.