Despite distinct clinical presentation and outcome, systemic, primary cutaneous, and breast implant-associated anaplastic large cell lymphomas (S-, PC-, BI-ALCL) ALK-negative (ALK-) show similar histopathological features including the presence of the "hallmark" cells with horseshoe-shaped nuclei and CD30 protein expression. The purpose was to better characterize these three entities using immunohistochemistry and FISH (Fluorescent in situ hybridization) to identify biomarkers differently expressed and that might be involved in their pathogenesis. Twenty-two S-ALCL ALK-, 13 PC-ALCL, and 2 BI-ALCL were included. Cases were tested for P53, P63, MUM1, MYC, GATA3, p-STAT3, PD1, and PDL1 protein expression and DUP22, TP53, TP63, MYC, and PDL1 chromosomal aberrations. As expected, S-ALCL ALK- patients had adverse outcome compare to PC and BI-ALCL. No difference was observed between the three groups concerning protein expression except for MUM1 that was significantly more frequently expressed in S-ALCL ALK- compared to PC-ALCL. In particular, constitutive activation of the STAT3 pathway and PDL1/PD1 immune-checkpoint expression was present in the three entities. TP53 deletion and PDL1 gene amplification were the commonest cytogenetic alterations and were present in the three entities. None of the studied biological parameters was associated with prognosis. Despite distinct clinical behavior, S-ALCL ALK-, PC-ALCL, and BI-ALCL share similar biological features. Larger series should be investigated with the current approach to determine more precisely the activity and the prognostic value of these biomarkers and pathways in each group.

A Disintegrin And Metalloprotease 23 (ADAM23), a member of the ADAM family, is involved in neuronal differentiation and cancer. ADAM23 is considered a possible tumor suppressor gene and is frequently downregulated in various types of malignancies. Its epigenetic silencing through promoter hypermethylation was observed in breast cancer (BC). In the present study, we evaluated the prognostic significance of ADAM23 promoter methylation for hematogenous spread and disease-free survival (DFS). Pyrosequencing was used to quantify ADAM23 methylation in tumors of 203 BC patients. Presence of circulating tumor cells (CTC) in their peripheral blood was detected by quantitative RT-PCR. Expression of epithelial (KRT19) or mesenchymal (epithelial-mesenchymal transition [EMT]-inducing transcription factors TWIST1, SNAI1, SLUG and ZEB1) mRNA transcripts was examined in CD45-depleted peripheral blood mononuclear cells. ADAM23 methylation was significantly lower in tumors of patients with the mesenchymal CTC (P = .006). It positively correlated with Ki-67 proliferation, especially in mesenchymal CTC-negative patients (P = .001). In low-risk patients, characterized by low Ki-67 and mesenchymal CTC absence, ADAM23 hypermethylation was an independent predictor of DFS (P = .006). Our results indicate that ADAM23 is likely involved in BC progression and dissemination of mesenchymal CTC. ADAM23 methylation has the potential to function as a novel prognostic marker and therapeutic target.

AIMS: This study sought to clarify the molecular pathways underlying the putative evolution from lymphomatoid papulosis (LyP) to cutaneous anaplastic large-cell lymphoma (c-ALCL) and lymph node invasion (LNI).
METHODS AND RESULTS: We analysed nine sequential tumours from the same patient presenting with parallel evolution of LyP (n = 3) and c-ALCL (n = 1) with LNI (n = 1), combined with systemic diffuse large B-cell lymphoma (DLBCL) (n = 4). Clonality analysis showed a common clonal T-cell origin in the five CD30+ lesions, and a common clonal B-cell origin in the four DLBCL relapses. Array-comparative genomic hybridisation and targeted next-generation sequencing analysis demonstrated relative genomic stability of LyP lesions as compared with clonally related anaplastic large-cell lymphoma (ALCL) tumours, which showed 4q and 22q13 deletions involving the PRDM8 and TIMP3 tumour suppressor genes, respectively. The three analysed CD30+ lesions showed mostly private (specific to each sample) genetic alterations, suggesting early divergence from a common precursor. In contrast, DLBCL tumours showed progressive accumulation of private alterations, indicating late divergence.
CONCLUSIONS: Sequential cutaneous and nodal CD30+ tumours were clonally related. This suggests that LyP, c-ALCL and LNI represent a continuous spectrum of clonal evolution emerging from a common precursor of cutaneous CD30+ lymphoproliferations. Therefore, nodal ALCL tumours in the context of LyP should be considered as a form of transformation rather than composite lymphoma.

Mycosis fungoides (MF) is an indolent cutaneous T-cell lymphoma and may transform into large cell lymphoma in the disease course. The incidence of MF in Taiwan is lower as compared to that in the West. In this study we aimed to characterise the clinicopathological, immunohistochemical, and genetic features of transformed MF (t-MF) in Taiwan. We retrospectively collected MF cases from April 2004 to April 2015 from four medical centres in Taiwan, reviewed the clinical history and histopathology, and performed immunohistochemistry, in situ hybridisation for EBV (EBER), and fluorescence in situ hybridisation (FISH) for DUSP22/MUM1 gene translocation. Fifty-one specimens from 32 patients with MF were identified with a male to female ratio of 1.5:1 and a median age of 50.5 (range 16-82). Tumours from 11 patients (34%) underwent large cell transformation, with the median age at 61 (range 26-82). The tumour cells of t-MF expressed CD30 and MUM1 in 82% and 100% cases, respectively. CD56 was expressed in two (10%) of 21 MF cases and two (18%) of 11 t-MF cases, respectively; and all four CD56-positive cases were of a helper T-cell phenotype. All CD56 expressing MF and t-MF tumours tested for EBER were negative. FISH study showed rearranged DUSP22/IRF4 in one (9%) of 11 t-MF cases, but not in any of the 19 non-transformed MF specimens. Four patients with t-MF died of disease and six were alive with disease in a median follow-up time of 25 months (mean 44.7 months). Large cell transformation and aberrant CD56 expression were more frequent in patients with MF in Taiwan compared to those in the West. Larger case series and/or national studies are needed to clarify the significance and impact of large cell transformation on the prognosis of patients with MF.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a cancer-causing virus in humans, primarily affecting AIDS patients. KSHV causes a range of cancers including Kaposi's sarcoma, pleural effusion lymphoma and multicentric Castleman's disease. Current methods available for treating these cancers are relatively ineffective, and new targets for therapy are needed. The KSHV viral homolog of interleukin-6 gene (vIL-6) may play a significant role in tumor development and may serve as a new anti-cancer target, but its role in tumor formation is only partially understood. Here, a novel animal model was used to study how vIL-6 affects tumor development. Highly immune-deficient Rag2-/-γc-/- mice were transplanted with an immortalized human B cell line (BJAB) harboring either wild-type (WT) KSHV or a mutant strain lacking vIL-6 ΔvIL-6). Solid tumors developed and total tumor mass and the number of tumors were characterized. The vIL-6 gene had no significant impact on tumor mass, but significantly more tumors were detected when vIL-6 was present. Significant differences in expression of B cell markers in cells from extracted tumors were detected based upon the presence of vIL-6. B cell markers in tumor cells were also compared to the same cell type in culture, prior to xenotransplantation; B cell markers were mostly downregulated during tumor formation and these changes did not differ based upon the presence of vIL-6. The only marker that significantly increased in expression during tumor development was CD30. Tumor blood vessels were quantified to determine if more angiogenesis occurred with vIL-6-expressing virus, but there was no significant difference. These data indicate that vIL-6 plays a role in KSHV tumor formation in B cells in vivo. Further investigation into how vIL-6 manipulates CD30 expression may shed insight into KSHV oncogenesis, and may identify how vIL-6 can be targeted.

Classic Hodgkin lymphoma (cHL) is one of the most common lymphomas in the Western world. Advances in the management of cHL have led to high cure rates exceeding 80%. Nevertheless, relapse or refractory disease in a subset of patients and treatment-related toxicity still represents unsolved clinical problems. The introduction of targeted treatments such as PD-1 blockade and the CD30 antibody drug conjugate, brentuximab vedotin, has broadened treatment options in cHL, emphasizing the critical need to identify biomarkers with the goal to provide rationales for treatment selection, increase effective drug utilization, and minimize toxicity. The unique biology of cHL featuring low abundant tumor cells and numerous nonmalignant immune cells in the tumor microenvironment can provide various types of promising biomarkers related to the tumor cells directly, tumor microenvironment cross-talk, and host immune response. Here, we comprehensively review novel biomarkers including circulating tumor DNA and gene expression-based prognostic models that might guide the ideal management of cHL in the future.

Anaplastic large cell lymphomas (ALCLs) are CD30-positive T-cell non-Hodgkin lymphomas broadly segregated into ALK-positive and ALK-negative types. Although ALK-positive ALCLs consistently bear rearrangements of the

BACKGROUND: Alpha-fetoprotein (AFP) is a useful tumor marker for ovarian germ cell tumors, particularly yolk sac tumor (YST). It is valuable for both diagnosis and further follow-up. Epithelial ovarian carcinoma (EOC) rarely secretes AFP, especially for clear cell type and in the postmenopausal women. Based on the limited knowledge about AFP-producing clear cell type EOC, a case and literature review on this topic is extensively reviewed.
CASE PRESENTATION: We report a 55-year-old postmenopausal woman experienced vaginal spotting for one month, and serum level of AFP was 60,721 ng/ml initially. Histological examination was clear cell type EOC. Tumor cells revealed strong immunoreactivity for glypican-3 (GPC3) and AFP and weak for hepatocyte nuclear factor-1 beta (HNF-1 beta), but negative for CD30, making the diagnosis of AFP-producing clear cell type EOC with fetal gut differentiation in focal areas, FIGO (International Federation of Gynecology and Obstetrics) IIIc. Although the patient underwent an intensive treatment, including optimal debulking surgery and multi-agent chemotherapy, the patient died of disease. To provide a better understanding of clinical and molecular characteristics of the AFP-producing clear cell type EOC, we conducted a systematic literature review.
CONCLUSIONS: A total of three papers described the AFP-producing clear cell type EOC are available. The overall survival rate of these cases, including the current case is 50%. Although immunohistochemical examination is not always needed in routine for the diagnosis of clear cell type EOC, to distinguish from other tumors, especially germ cell tumors, or to provide the better way to monitor therapeutic response or to evaluate the disease status, immunostaining, including GPC3, HNF-1 beta, CD30, cytokeratin 7 or 20, and AFP is taken into account. Due to rarity, the appropriate chemotherapy regimen and the biological behavior of AFP-producing clear cell type EOC are still unclear.

Anaplastic large-cell lymphoma (ALCL) was first described in 1985 by Stein et al and is a clinically, morphologically, and immunophenotypically heterogeneous neoplasm characterized by ALK expression, rearrangement of the ALK gene, and most characteristically its occurrence in children. Clinically, cutaneous ALK+ ALCL can be divided into primary (cutaneous forms) and the much more common, secondary dissemination by a systemic lymphoma. Systemic ALK+ ALCL represents 10%-15% of childhood non-Hodgkin lymphoma and generally presents with advanced systemic disease. Here, we describe a case of a 9-year-old girl who presented with a solitary ulcerated nodule on the elbow that clinically resembled a pyogenic granuloma yet showed ALK, CD30, and myeloperoxidase expression. Fluorescent in situ hybridization with a break-apart probe for ALK revealed the presence of an ALK gene rearrangement. The initial workup showed no evidence of extracutaneous malignancy, and a diagnosis of primary cutaneous ALK+ ALCL was favored. Subsequent imaging studies revealed mediastinal lymphadenopathy, compatible with a systemic form of T-cell lymphoma, treated subsequently with chemotherapy. This report highlights the importance of an adequate systemic evaluation on the presentation of a cutaneous form of ALK+ ALCL.

Pityriasis lichenoides (PLs) is an uncommon skin disease of unknown etiology. In recent years, an atypical form of PL has been described, showing overlapping features with mycosis fungoides (MF) and lymphomatoid papulosis. We studied 66 patients with an initial histopathologic diagnosis of PL (M:F=34:32; median age, 25 y; range, 7 to 85 y). According to clinical and phenotypic features, cases were classified into 4 categories: (1) Conventional PL (characteristic clinical features of PL without phenotypic aberrations) (n=20; M:F=8:12; median age, 37 y; range, 9 to 74 y); (2) Atypical form of PL (characteristic clinical features of PL with phenotypic aberrations) (n=25; M:F=16:9; median age, 21 y; range, 7 to 72 y). Four of these patients subsequently developed MF; (3) Lymphomatoid papulosis (waxing and waning lesions and positivity for CD30) (n=10; M:F=4:6; median age, 41 y; range, 16 to 83 y); (4) MF (clinical features typical of MF) (n=11; M:F=6:5; median age, 17 y; range, 8 to 85 y). Molecular analyses of clonality of the infiltrate did not reveal relevant differences among these 4 groups. Our study suggests that patients with an initial histopathologic diagnosis of PL may belong to different groups, showing that clinicopathologic correlation and complete phenotypic analyses are paramount in order to achieve proper classification. Although the relationship between PL and MF is yet a matter of debate, at the present state of knowledge, patients with a clinicopathologic presentation consistent with PL but with aberrant phenotypic features should be monitored in order to detect a possible evolution into MF.

BACKGROUND: Epithelioid cell histiocytoma (ECH), which is also known as epithelioid benign fibrous histiocytoma, has been classified as a rare variant of fibrous histiocytoma (FH). However, the recent detection of ALK protein expression and/or ALK gene rearrangement in ECH suggests that it might be biologically different from conventional FH.
CASE PRESENTATION: A 27-year-old male presented with nodule on his left foot, which had been present for 5 years. A macroscopic examination revealed an exophytic, hyperkeratotic nodule on the dorsum of the left foot. Tumorectomy was performed, and a microscopic examination showed a subepidermal lesion composed of sheets of tumor cells with oval to round nuclei and ill-defined eosinophilic cytoplasm. The tumor cells were diffusely positive for factor XIIIa and ALK, but were negative for AE1/AE3 keratin, alpha-smooth muscle actin, CD30, CD34, CD68, PU.1, melan A, MITF, and S-100 protein. ALK immunostaining showed a diffuse cytoplasmic staining pattern. ALK fluorescence in situ hybridization demonstrated break-apart signals, which was suggestive of ALK rearrangement. A 5'-rapid amplification of cDNA ends assay detected SQSTM1-ALK fusion, in which exon 5 of the SQSTM1 gene was fused to exon 20 of the ALK gene. The patient was free from recurrence and distant metastasis at the 1-year of follow-up.
CONCLUSION: We were able to demonstrate the SQSTM1-ALK fusion gene in ECH. Practically, detecting immunopositivity for ALK and appropriate cell-lineage markers are the key to diagnosing ECH.

AIM: CD30+ diffuse large B-cell lymphoma (DLBCL) has emerged as a new immunophenotypic variant of
METHODS: A total of 241 patients with
RESULTS: Using a >0% threshold, CD30 expression was detected in approximately 10% patient with
CONCLUSION: CD30+ DLBCL may be a subset of

The BIOMED-2 PCR protocols targeting IGH and IGK genes may be useful for detecting clonality in Hodgkin lymphoma (HL). The clonality detection rates, however, have not been very high with these methods using paraffin-embedded tumor sections. We previously described the usefulness of the semi-nested BIOMED-2 IGH assay in B-cell malignancies. In this study, we devised a novel semi-nested BIOMED-2 IGK assay. Employing 58 cases of classical HL, we carried out the standard BIOMED-2, BIOMED-2 followed by BIOMED-2 re-amplification, and BIOMED-2 followed by semi-nested BIOMED-2, all targeting IGH and IGK, using paraffin-embedded tissues. In both IGH and IGK assays, semi-nested assays yielded significantly higher clonality detection rates than the standard assays and re-amplification assays. Clonality was detected in 13/58 (22.4%) classical HL cases using the standard IGH/IGK assays while it was detected in 38/58 (65.5%) cases using semi-nested IGH/IGK assays. The detection rates were not associated with the HL subtypes, CD30-positive cell density, CD20-positive cell density, or Epstein-Barr virus (EBV) positivity. In conclusion, tumor clonality was detected in nearly two-thirds of classical HL cases using semi-nested BIOMED-2 IGH/IGK assays using paraffin tumor sections. These semi-nested assays may be useful when the standard IGH/IGK assays fail to detect clonality in histopathologically suspected HLs.

Mycosis fungoides in palmoplantar localization (MFPP) is a rare variant of MF that is confined to the hands and feet. Patients commonly receive treatment over many years for suspected palmoplantar dermatitis before the diagnosis is made. Most MFPP patients remain at patch or plaque stage, and often respond to treatment with radiotherapy. Herein, we describe a 77-year-old man who suffered 6 years of hand and foot dermatitis that failed multiple treatments, most notably TNF-α inhibitors and mycophenolate mofetil. He eventually developed a tumor on the hand, which was biopsied to reveal a dense dermal infiltrate of large lymphocytes (CD3+/CD4-/CD8-/TCR-BetaF1+/partial CD30+). A subsequent biopsy of an eczematous patch from his hand revealed an epidermotropic and syringotropic infiltrate comprised of smaller lymphocytes with a concordant immunophenotype and matching clonal peak with TCR gene rearrangement. He was diagnosed with MFPP and started on radiotherapy with a modest response; therefore, a decision was made to start brentuximab vedotin, which resulted in a complete response. MFPP is an exceedingly rare variant of MF that can show large-cell transformation and progress in stage. We highlight a possible association between disease progression and immunosuppressants and the potential role for treatment with brentuximab.

Cutaneous CD30

This phase 1 study evaluated frontline brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (BV+CHP; 6 cycles, then up to 10 cycles of brentuximab vedotin monotherapy) in 26 patients with CD30

Adult T-cell leukemia/lymphoma, an aggressive T-cell neoplasm, is causally linked to human T-cell lymphotropic virus type 1 and based on this association has a distinct geographic distribution. In our United States-based practice, whose population is enriched for immigrants from human T-cell lymphotropic virus type 1 endemic areas, we have identified that a subset of adult T-cell leukemia/lymphoma, in the absence of human T-cell lymphotropic virus type 1 identification, are indistinguishable from other more common T-cell neoplasms. We retrospectively gathered serology results for anti-human T-cell lymphotropic virus type 1/2 antibody in patients diagnosed with T-cell neoplasms at our institution. A total of 220 human T-cell lymphotropic virus type 1/2 positive patients with T-cell neoplasms were identified; 199 (91%) were correctly classified as adult T-cell leukemia/lymphoma or provisionally as peripheral T-cell lymphoma (serology testing pending). Twenty-one cases (9%) were initially misclassified, including the following: 13 presenting with skin +/- peripheral blood involvement and misclassified as mycosis fungoides/Sezary syndrome; 7 with lymphomatous disease, absence of leukemic involvement, and diffuse CD30 expression, misclassified as ALK- negative anaplastic large-cell lymphoma; 1 thought to represent T-prolymphocytic leukemia with TCL-1 gene rearrangement and diffuse marrow involvement. We also present an example of adult T-cell leukemia/lymphoma, which mimicked lymphoepithelioid variant of peripheral T-cell lymphoma also with diffuse marrow involvement. A subset of adult T-cell leukemia/lymphoma can closely mimic a variety of other more common T-cell neoplasms. Due to its extreme clinicopathologic heterogeneity, identification of adult T-cell leukemia/lymphoma requires a high level of suspicion based on patient demographic alone, which should prompt anti-human T-cell lymphotropic virus type 1/2 serology testing in all T-cell neoplasms developing in patients of appropriate demographic. Absence of high level of suspicion, adult T-cell leukemia/lymphoma is easily misclassified.

Composite lymphoma is defined as the co-occurrence of two types of lymphoma, comprising 1-4% of lymphomas, and the association of B-cell-type chronic lymphocytic leukemia (B-CLL)/small lymphocytic lymphoma and peripheral T-cell lymphoma (PTCL) is rare. Here, we report a case (77-year-old woman) of advanced B-CLL complicated by newly appearing PTCL. Two years after the onset of B-CLL, CLL cells acquired CD38 antigen expression and the disease entity became CLL/prolymphocytic leukemia. Trisomy 12 and t(14;18) karyotypes were observed. Five years after the onset of B-CLL, large abnormal cells with convoluted nuclei appeared in the peripheral blood and rapidly increased in number. These cells were positive for CD3, CD4, CD5, CD30 (partially), CD56, and αβ-type T-cell receptor (TCR), in which PCR demonstrated monoclonal TCR-γ gene rearrangement. An additional diagnosis of PTCL, not otherwise specified was made. We treated her with an R-CHOP regimen, resulting in the marked reduction of B-CLL cells but progressive PTCL. Brentuximab vedotin had a transient effect, but the patient died of sepsis due to residual PTCL and pancytopenia. This case is highly informative for tumor biology of B-CLL in terms of emergence of both chromosomal abnormalities and PTCL with progression of this leukemia.

PURPOSE OF REVIEW: Peripheral T cell lymphoma is a rare heterogeneous group of diseases which are characterized by poor outcomes to treatment and short overall survival. In the past decade, several new therapies targeting T cell biology have been approved in the relapsed setting. These new therapies, such as pralatrexate, romidepsin, belinostat, and brentuximab vedotin, have begun to make their way into practice. Despite these advances, outcomes have not changed dramatically. In recent years, efforts have been made to incorporate these new therapies into combination strategies to treat this challenging disease entity. Herein we will review some of the latest developments.
RECENT FINDINGS: With the new WHO classification, discrete entities of PTCL are now being identified by molecular and phenotypic markers. This new classification is critical to our ability to define disease entities which may respond to certain classes of targeted therapy. Some such mutations include genes controlling epigenetics (TET2, IDH2, DNMT3A, RHOA, CD28). As such, epigenetic therapies such as histone deacetylase (HDAC) inhibitors have become the platform to which other novel therapies or chemotherapy has been added. Early phase clinical studies have demonstrated that combination therapy with romidepsin plus other agents known to have activity in T cell lymphoma have enhanced clinical benefit for this group of diseases. In addition, the antibody drug conjugate, brentuximab vedotin has been shown to have potent activity in T cell lymphomas expressing CD30. This drug is being studied as well with other targeted therapies and chemotherapy in an effort to improve response rates and progression-free survival. Although T cell lymphomas remain a highly challenging group of diseases to treat, new efforts to leverage drugs that discretely target the biology that drives T cell lymphomagenesis in combination provide hope that improved outcomes may be realized in the near future.

BACKGROUND: The programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway inhibits the activation of T cells and plays a crucial role in the negative regulation of cellular and humoral immune responses. Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. In the present study, we aimed to detect the expression of PD-L1 in DLBCL and to analyze its relationship with prognosis.
METHODS: We reviewed medical records of 204 newly diagnosed DLBCL patients in Sun Yat-sen University Cancer Center between October 2005 and August 2012. The expression of PD-L1 in tumor tissues from these 204 patients was detected using immunohistochemical (IHC) assay. The expression of anaplastic lymphoma kinase (ALK), CD5, CD30, and C-Myc in tumor specimens from 109 patients was detected using IHC, and Epstein-Barr virus (EBV)-encoded RNAs (EBERs) were detected using fluorescence in situ hybridization. The Spearman method was used for correlation analysis. The Kaplan-Meier method with log-rank test was used for univariate analysis. Cox proportional hazards model was used for multivariate analysis.
RESULTS: Of the 204 patients, 100 (49.0%) were PD-L1-positive in tumor cells and 44 (21.6%) were PD-L1-positive in tumor microenvironment. PD-L1 expression in tumor cells and tumor microenvironment were more common in the non-germinal center B-cell-like (GCB) subtype than in the GCB subtype (P = 0.02 and P = 0.04). Patients with PD-L1 expression in tumor microenvironment were more likely to be resistant to first-line chemotherapy when compared with the patients without PD-L1 expression in tumor microenvironment (P = 0.03). PD-L1 expression in tumor microenvironment was negatively correlated with C-Myc expression (r = - 0.20, P = 0.04). No correlations were detected between PD-L1 expression and the expression of ALK, CD5, and CD30 as well as EBERs. The 5-year overall survival (OS) rates were 50.0% and 67.3% in patients with and without PD-L1 expression in tumor cells (P = 0.02). PD-L1 expression in tumor cells was an independent risk predictor for OS (P < 0.01).
CONCLUSIONS: PD-L1 expression is more common in the non-GCB subtype than in the GCB subtype. PD-L1 expression in tumor microenvironment has a negative correlation with C-Myc. PD-L1 positivity predicts short survival in DLBCL patients. For patients with PD-L1 expression, more strategy such as anti-PD-L1 antibody treatment should be recommended.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma entity with an incidence of 0.1 to 0.2/100 000/y. Compared with the more common subtypes of classical Hodgkin lymphoma, NLPHL is characterized by distinct pathological and clinical features. Histologically, the disease-defining lymphocyte predominant cells consistently express CD20 but lack CD30. Clinically, NLPHL mostly has a rather indolent course, and patients usually are diagnosed in early stages. The prognosis of early-stage NLPHL is excellent, with progression-free survival and overall survival rates exceeding 90% after involved-field radiotherapy (IF-RT) alone (stage IA) or combined modality treatment consisting of a brief chemotherapy with 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy followed by IF-RT (early stages other than stage IA). In contrast, patients with advanced disease at diagnosis tend to relapse either with NLPHL histology or with histological transformation into aggressive B-cell non-Hodgkin lymphoma despite more aggressive first-line treatment with 6 to 8 cycles of multiagent chemotherapy. However, even NLPHL patients with multiple relapses successfully respond to salvage therapy in many cases. Salvage therapies range from single-agent anti-CD20 antibody treatment to high-dose chemotherapy followed by autologous stem cell transplantation. Treatment at disease recurrence should be chosen on the basis of various factors, including histology at relapse, time to relapse, extent of disease at relapse, and prior treatment. Because death among NLPHL patients is more often caused by therapy-related late effects than lymphoma-related complications, optimizing the risk-benefit ratio of treatment by decreasing toxicity whenever possible is the major goal of clinical research in this disease.

Indoleamine 2,3-dioxygenase 1 (IDO) is an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway. The purpose of the present study was to determine the clinical significance of Trp catabolism in newly diagnosed Hodgkin lymphoma (HL) patients. We quantified serum Trp and Kyn in 52 HL patients, and analyzed their associations with different clinical parameters including serum soluble CD30 concentration. The IDO expression was evaluated in the patients' affected lymph nodes. The cohort comprised 22 male and 30 female patients (age range, 15-81 years; median, 45 years), with a 5-year overall survival (OS) of 88.6%. The OS was significantly shorter for patients with a high Kyn/Trp ratio (OS at 5 years, 60.0% vs 92.2%), for those with stage IV disease, and for those with lymphocytopenia (<600/mm

A number of studies have recently demonstrated that super-enhancers, which are large cluster of enhancers typically marked by a high level of acetylation of histone H3 lysine 27 and mediator bindings, are frequently associated with genes that control and define cell identity during normal development. Super-enhancers are also often enriched at cancer genes in various malignancies. The identification of such enhancers would pinpoint critical factors that directly contribute to pathogenesis. In this study, we performed enhancer profiling using primary leukemia samples from adult T-cell leukemia/lymphoma (ATL), which is a genetically heterogeneous intractable cancer. Super-enhancers were enriched at genes involved in the T-cell activation pathway, including

The Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma (HL) are characterised by the aberrant activation of multiple signalling pathways. Here we show that a subset of HL displays altered expression of sphingosine-1-phosphate (S1P) receptors (S1PR)s. S1P activates phosphatidylinositide 3-kinase (PI3-K) in these cells that is mediated by the increased expression of S1PR1 and the decreased expression of S1PR2. We also showed that genes regulated by the PI3-K signalling pathway in HL cell lines significantly overlap with the transcriptional programme of primary HRS cells. Genes upregulated by the PI3-K pathway included the basic leucine zipper transcription factor, ATF-like 3 (BATF3), which is normally associated with the development of dendritic cells. Immunohistochemistry confirmed that BATF3 was expressed in HRS cells of most HL cases. In contrast, in normal lymphoid tissues, BATF3 expression was confined to a small fraction of CD30-positive immunoblasts. Knockdown of BATF3 in HL cell lines revealed that BATF3 contributed to the transcriptional programme of primary HRS cells, including the upregulation of S1PR1. Our data suggest that disruption of this potentially oncogenic feedforward S1P signalling loop could provide novel therapeutic opportunities for patients with HL.

BACKGROUND: Targeting CD30 with monoclonal antibodies in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) has had profound clinical success. However, adverse events, mainly mediated by the toxin component of the conjugated antibodies, cause treatment discontinuation in many patients. Targeting CD30 with T cells expressing a CD30-specific chimeric antigen receptor (CAR) may reduce the side effects and augment antitumor activity.
METHODS: We conducted a phase I dose escalation study in which 9 patients with relapsed/refractory HL or ALCL were infused with autologous T cells that were gene-modified with a retroviral vector to express the CD30-specific CAR (CD30.CAR-Ts) encoding the CD28 costimulatory endodomain. Three dose levels, from 0.2 × 108 to 2 × 108 CD30.CAR-Ts/m2, were infused without a conditioning regimen. All other therapy for malignancy was discontinued at least 4 weeks before CD30.CAR-T infusion. Seven patients had previously experienced disease progression while being treated with brentuximab.
RESULTS: No toxicities attributable to CD30.CAR-Ts were observed. Of 7 patients with relapsed HL, 1 entered complete response (CR) lasting more than 2.5 years after the second infusion of CD30.CAR-Ts, 1 remained in continued CR for almost 2 years, and 3 had transient stable disease. Of 2 patients with ALCL, 1 had a CR that persisted 9 months after the fourth infusion of CD30.CAR-Ts. CD30.CAR-T expansion in peripheral blood peaked 1 week after infusion, and CD30.CAR-Ts remained detectable for over 6 weeks. Although CD30 may also be expressed by normal activated T cells, no patients developed impaired virus-specific immunity.
CONCLUSION: CD30.CAR-Ts are safe and can lead to clinical responses in patients with HL and ALCL, indicating that further assessment of this therapy is warranted.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01316146.
FUNDING: National Cancer Institute (3P50CA126752, R01CA131027 and P30CA125123), National Heart, Lung, and Blood Institute (R01HL114564), and Leukemia and Lymphoma Society (LLSTR 6227-08).

BACKGROUND: Histologic prognostic factors have been described for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). This study examines histologic and immunophenotypic variants in a clinical trial for pediatric NLPHL.
PROCEDURE: One hundred sixty-eight cases of localized NLPHL were examined for histologic variants, CD30 and immunoglobulin D (IgD) expression, and outcome. Histologic types were scored categorically as 0 = 0, 1 ≤ 25%, and 2 > 25% of the sample.
RESULTS: Fifty-eight (35.1%) cases showed only typical nodular with or without serpiginous histology (types A and B). The remainder showed mixtures of histologies. The numbers of patients with score 2 are 85 (50.6%) type A, 21 (12.5%) type B, 46 (27.4%) with extranodular large B cells (type C), 3 with T-cell-rich nodular pattern (type D), 55 (32.7%) with diffuse T-cell-rich (type E) pattern, and 2 (1.2%) with diffuse B-cell pattern (type F). Higher level of types C (P = 0.048) and D (P = 0.033) resulted in lower event-free survival (EFS). Cytoplasmic IgD was found in 65 of 130 tested (50%), did not significantly associate with EFS but positively correlated with types C and E histology (P < 0.0001) and negatively correlated with types A (P = 0.0003) and B (P = 0.006). Seventeen (10%) expressed CD30, with no adverse effect.
CONCLUSIONS: Variant histology is common in pediatric NLPHL, especially types C and E, which are associated with IgD expression. Type C variant histology and possibly type D are associated with decreased EFS, but neither IgD nor CD30 are adverse features. Variant histology may warrant increased surveillance, but did not affect overall survival.

Late breast implant seroma may be the presentation of a breast implant-associated anaplastic large cell lymphoma (BI-ALCL), which claims for a prompt recognition. However, BI-ALCL diagnosis on fine-needle aspiration (FNA) might be challenging for pathologists lacking experience with peri-implant breast effusions. Sixty-seven late breast implant seromas collected by FNA from 50 patients were evaluated by Papanicolaou smear stain and immunocytochemistry on cell blocks. A diagnostic algorithm based on the cellular composition, cell morphology and percentage of CD30+ cells was developed. Histological evaluation of the corresponding peri-prosthetic capsules was also performed. Most of the effusions (91% of the samples) were classified as reactive and 9% as BI-ALCL. In the BI-ALCL cases, medium-to-large atypical cells expressing CD30 represented more than 70% of the cellularity, whereas in in the reactive effusions CD30+ elements were extremely rare (<5%) and consisted of non-atypical elements. The reactive effusions were categorized into three patterns: i) acute infiltrate with prominent neutrophilic component (33% of the samples); ii) mixed infiltrate characterized by a variable number of neutrophils, lymphocytes and macrophages (30% of the samples); iii) chronic infiltrate composed predominantly of T lymphocytes or macrophages with only sporadic granulocytes (37% of the samples). The inflammatory cytological patterns were consistent with the histology of the corresponding capsules. Our results indicate that cytological analysis of late breast implant effusions, supported by the knowledge of the heterogeneous cytomorphological spectrum of late seromas, is a valuable approach for the early recognition of BI-ALCL.

Primary gastrointestinal anaplastic large cell lymphoma (GI-ALCL) is rare. We report eight new cases. The median age was 61.5 years (range 10-88), most frequently involving the stomach (n = 3) and small intestine (n = 4). The neoplastic hallmark cells in all cases expressed CD30. Anaplastic lymphoma kinase (ALK) protein was expressed in two cases (25%). By in situ hybridisation, all cases were negative for Epstein-Barr virus and for DUSP22/IRF4 gene translocation. At a median follow-up time of 37.5 months, four patients died of disease, one was alive with disease, and three were disease-free. Our literature review showed that GI-ALCL occurred mainly in older patients and was characterised by a low rate of ALK expression, a high rate of T-cell lineage, and a frequent occurrence in the small intestine. Incorporating our two ALK

Pediatric fibroblastic/myofibroblastic lesions are a relatively common group of tumors with varying morphologies, for which the molecular mechanisms are becoming increasingly well characterized. Congenital infantile fibrosarcoma (CIFS), perhaps the most well studied of these lesions is characterized by a recurrent ETV6-NTRK3 gene fusion. However, a notable subset of locally aggressive congenital/infantile soft tissue lesions with similar morphologic features to CIFS, have not to-date, shown evidence of any canonical molecular aberration. We describe 6 patients with mesenchymal tumors composed of infiltrative fibroblastic/myofibroblastic tumor cells and showing a morphologic spectrum of features much analogous to that previously described in CIFS but without ETV6 fusion transcripts. These tumors lacked a uniform immunoprofile, but showed variable expression of CD34, S100, smooth muscle actin, and CD30. All patients first developed a mass in infancy (≤2 months of age). Using next-generation DNA sequencing, TMP3-NTRK1 fusions were identified in 4 cases, an LMNA-NTRK1 fusion in one case, and a variant EML4-NTRK3 fusion in one case. Similar to infantile fibrosarcoma, these tumors were locally aggressive (with local recurrences if incompletely excised) and rarely metastasized (lung metastases in one patient). Proper identification of these tumors including investigation for NTRK family gene rearrangements is essential for diagnostic accuracy, as well as for clinical management decisions. Given the morbidity associated with radical resection of large soft tissue tumors, children with unresectable, recurrent, and/or metastatic disease may benefit from treatment with NTRK targeted therapies.

Classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) feature high expression of activator protein-1 (AP-1) transcription factors, which regulate various physiological processes but also promote lymphomagenesis. The AP-1 factor basic leucine zipper transcription factor, ATF-like 3 (BATF3), is highly transcribed in cHL and ALCL; however, its functional importance in lymphomagenesis is unknown. Here we show that proto-typical CD30