Generation and External Validation of a Histologic Transformation Risk Model for Patients with Follicular Lymphoma.

Follicular lymphoma (FL) is the most frequent indolent lymphoma. Some patients (10%-15%) experience histologic transformation (HT) to a more aggressive lymphoma, usually diffuse large B-cell lymphoma (DLBCL). This study aimed to validate and improve a genetic risk model to predict HT at diagnosis.We collected mutational data from diagnosis biopsies of 64 FL patients. We combined them with the data from a previously published cohort (total n = 104; 62 from nontransformed and 42 from patients who did transform to DLBCL). This combined cohort was used to develop a nomogram to estimate the risk of HT. Prognostic mutated genes and clinical variables were assessed using Cox regression analysis to generate a risk model. The model was internally validated by bootstrapping and externally validated in an independent cohort. Its performance was evaluated using a concordance index and a calibration curve. The clinicogenetic nomogram included the mutational status of 3 genes (HIST1HE1, KMT2D, and TNFSR14) and high-risk Follicular Lymphoma International Prognostic Index and predicted HT with a concordance index of 0.746. Patients were classified as being at low or high risk of transformation. The probability HT function at 24 months was 0.90 in the low-risk group vs 0.51 in the high-risk group and, at 60 months, 0.71 vs 0.15, respectively. In the external validation cohort, the probability HT function in the low-risk group was 0.86 vs 0.54 in the high-risk group at 24 months, and 0.71 vs 0.32 at 60 months. The concordance index in the external cohort was 0.552. In conclusion, we propose a clinicogenetic risk model to predict FL HT to DLBLC, combining genetic alterations in HIST1H1E, KMT2D, and TNFRSF14 genes and clinical features (Follicular Lymphoma International Prognostic Index) at diagnosis. This model could improve the management of FL patients and allow treatment strategies that would prevent or delay transformation.

BCL3 rearrangements in B-cell lymphoid neoplasms occur in two breakpoint clusters associated with different diseases.

The t(14;19)(q32;q13) often juxtaposes BCL3 with immunoglobulin heavy chain (IGH) resulting in overexpression of the gene. In contrast to other oncogenic translocations, BCL3 rearrangement (BCL3-R) has been associated with a broad spectrum of lymphoid neoplasms. Here we report an integrative whole-genome sequence, transcriptomic, and DNA methylation analysis of 13 lymphoid neoplasms with BCL3-R. The resolution of the breakpoints at single base-pair revealed that they occur in two clusters at 5' (n=9) and 3' (n=4) regions of BCL3 associated with two different biological and clinical entities. Both breakpoints were mediated by aberrant class switch recombination of the IGH locus. However, the 5' breakpoints (upstream) juxtaposed BCL3 next to an IGH enhancer leading to overexpression of the gene whereas the 3' breakpoints (downstream) positioned BCL3 outside the influence of the IGH and were not associated with its expression. Upstream BCL3-R tumors had unmutated IGHV, trisomy 12, and mutated genes frequently seen in chronic lymphocytic leukemia (CLL) but had an atypical CLL morphology, immunophenotype, DNA methylome, and expression profile that differ from conventional CLL. In contrast, downstream BCL3-R neoplasms were atypical splenic or nodal marginal zone lymphomas (MZL) with mutated IGHV, complex karyotypes and mutated genes typical of MZL. Two of the latter four tumors transformed to a large B-cell lymphoma. We designed a novel fluorescence in situ hybridization assay that recognizes the two different breakpoints and validated these findings in 17 independent tumors. Overall, upstream or downstream breakpoints of BCL3-R are mainly associated with two subtypes of lymphoid neoplasms with different (epi)genomic, expression, and clinicopathological features resembling atypical CLL and MZL, respectively.

Peripheral T-cell lymphoma with a T follicular-helper phenotype: A different entity? Results of the Spanish Real-T study.

Nodal peripheral T-cell lymphoma (PTCL) with a T follicular helper phenotype (PTCL-TFH) is a new type of PTCL. We aimed to define its clinical characteristics and prognosis compared to PTCL not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL). This retrospective observational study included 175 patients diagnosed with PTCL between 2008 and 2013 in 13 Spanish sites. Patient diagnosis was centrally reviewed, and patients were reclassified according to the World Health Organization (WHO) 2016 criteria: 21 patients as PTCL-NOS, 55 as AITL and 23 as PTCL-TFH. Median follow-up was 56.07 months (95% CI 38.7-73.4). Progression-free survival (PFS) and overall survival (OS) were significantly higher in patients with PTCL-TFH than in those with PTCL-NOS and AITL (PFS, 24.6 months vs. 4.6 and 7.8 months, respectively, p = 0.002; OS, 52.6 months vs. 10.0 and 19.3 months, respectively, p < 0.001). Histological diagnosis maintained an independent influence on both PFS (hazard ratio [HR] 4.1 vs. PTCL-NOS, p = 0.008; HR 2.6 vs. AITL, p = 0.047) and OS (HR 5.7 vs. PTCL-NOS, p = 0.004; HR 2.6 vs. AITL, p = 0.096), regardless of the International Prognostic Index. These results suggest that PTCL-TFH could have more favourable features and prognosis than the other PTCL subtypes, although larger series are needed to corroborate these findings.

Extranodal natural killer/T-cell lymphoma nasal type in a western population: Molecular profiling identifies new therapeutic targets.

(A) Correlation matrix of unsupervised co-regulated genes, based on the 208 genes included in the NanoString platform. Some of the clusters of co-regulated genes corresponded to the following: Inflammatory cells; Epstein-Barr virus; B-cells; Cytotoxic T-cells; T-cells; and Proliferation. (B) Analysis of genomic alterations by targeted sequencing. Distribution of mutations in the 62 analyzed genes. Rows correspond to sequenced genes, columns represent individual patients. Color coding: green, missense; blue, synonymous; pink, frameshift; violet, Indel; red, stop gained; yellow, UTR.

Clinico-biological features and outcome of patients with splenic marginal zone lymphoma with histological transformation.

We describe 36 patients with splenic marginal zone lymphoma (SMZL) with transformation (SMZL-T), including 15 from a series of 84 patients with SMZL diagnosed at the Hospital Clinic of Barcelona (HCB) and 21 diagnosed with SMZL-T in other centres. In the HCB cohort, the cumulative incidence of transformation at 5 years was 15%. Predictors for transformation were cytopenias, hypoalbuminaemia, complex karyotype (CK) and both the Intergruppo Italiano Linfomi (ILL) and simplified Haemoglobin, Platelet count, lactate dehydrogenase (LDH) and extrahilar Lymphadenopathy (HPLL)/ABC scores (P < 0·05). The only independent predictor for transformation in multivariate analysis was CK [hazard ratio (HR) 4·025, P = 0·05]. Patients with SMZL-T had a significantly higher risk of death than the remainder (HR 3·89, P < 0·001). Of the 36 patients with SMZL-T, one developed Hodgkin lymphoma and 35 a diffuse large B-cell lymphoma, 71% with a non-germinal centre phenotype. The main features were B symptoms, lymphadenopathy, and high serum LDH. CK was observed in 12/22 (55%) SMZL-T and fluorescence in situ hybridisation detected abnormalities of MYC proto-oncogene, basic helix-loop-helix transcription factor (MYC), B-cell leukaemia/lymphoma 2 (BCL2) and/or BCL6 in six of 14 (43%). In all, 21 patients received immunochemotherapy, six chemotherapy, one radiotherapy and three splenectomy. The complete response (CR) rate was 61% and the median survival from transformation was 4·92 years. Predictors for a worse survival in multivariate analysis were high-risk International Prognostic Index (HR 5·294, P = 0·016) and lack of CR (HR 2·67, P < 0·001).

Genetic and phenotypic characterisation of HIV-associated aggressive B-cell non-Hodgkin lymphomas, which do not occur specifically in this population: diagnostic and prognostic implications.

The frequency of aggressive subtypes of B-cell non-Hodgkin lymphoma (B-NHL), such as high-grade B-cell lymphomas (HGBL) with MYC and BCL2 and/or BCL6 rearrangement (HGBL-DH/TH) or Burkitt-like lymphoma (BL) with 11q aberration, is not well known in the HIV setting. We aimed to characterise HIV-associated aggressive B-NHL according to the 2017 WHO criteria, and to identify genotypic and phenotypic features with prognostic impact. Seventy-five HIV-associated aggressive B-NHL were studied by immunohistochemistry (CD10, BCL2, BCL6, MUM1, MYC, and CD30), EBV-encoded RNAs (EBERs), and fluorescence in situ hybridisation (FISH) to evaluate the status of the MYC, BCL2, and BCL6 genes and chromosome 11q. The 2017 WHO classification criteria and the Hans algorithm, for the cell-of-origin classification of diffuse large B-cell lymphomas (DLBCL), were applied. In DLBCL cases, the frequencies of MYC and BCL6 rearrangements (14.9 and 27.7%, respectively) were similar to those described in HIV-negative patients, but BCL2 rearrangements were infrequent (4.3%). MYC expression was identified in 23.4% of DLBCL cases, and coexpression of MYC and BCL2 in 13.0%, which was associated with a worse prognosis. As for BL cases, the expression of MUM1 (30.4%) conferred a worse prognosis. Finally, the prevalence of HGBL-DH/TH and BL-like with 11q aberration are reported in the HIV setting. The phenotypic and genotypic characteristics of HIV-associated aggressive B-NHL are similar to those of the general population, except for the low frequency of BCL2 rearrangements in DLBCL. MYC and BCL2 coexpression in DLBCL, and MUM-1 expression in BL, have a negative prognostic impact on HIV-infected individuals.

Clonal relationship in multisited mucosa-associated lymphoid tissue lymphomas: a single-centre experience.

Clonal heterogeneity in multisited or recurrent lymphoid neoplasms is a phenomenon that has been increasingly studied in recent years. However, in mucosa-associated lymphoid tissue (MALT) lymphomas it remains largely unexplored. Patients diagnosed at our institution with multisited MALT lymphoma, from January 2009 to October 2018, were studied. Molecular studies were performed for the detection of clonally rearranged immunoglobulin by polymerase chain reaction.In all, 91 patients were included. Of those, 28 had a multisited disease and in 16 clonality studies were done. In eight cases, multifocal involvement was synchronous and in eight metachronous. Patients with non-gastric gastrointestinal tract involvement tended to disseminate within the same tract, without observing other specific dissemination patterns. Four cases (25%) had clonal heterogeneity at the different organs involved. All patients with late relapses (two patients) had different clones. The majority of patients with multisited MALT lymphomas presented with the same clone in the different involved organs, identifying a different clone in those with late relapses. These patients could represent de novo neoplasms, rather than a relapse. This could mean that some individuals might have a genetic predisposition to develop this type of lymphoma and it could also have clinical implications regarding therapeutic decisions.

Clinical and pathological characteristics of peripheral T-cell lymphomas in a Spanish population: a retrospective study.

We investigated the clinicopathological features and prognostic factors of patients with peripheral T-cell lymphoma (PTCL) in 13 sites across Spain. Relevant clinical antecedents, CD30 expression and staining pattern, prognostic indices using the International Prognostic Index and the Intergruppo Italiano Linfomi system, treatments, and clinical outcomes were examined. A sizeable proportion of 175 patients had a history of immune-related disorders (autoimmune 16%, viral infections 17%, chemo/radiotherapy-treated carcinomas 19%). The median progression-free survival (PFS) and overall survival (OS) were 7·9 and 15·8 months, respectively. Prognostic indices influenced PFS and OS, with a higher number of adverse factors resulting in shorter survival (P < 0·001). Complete response (CR) to treatment was associated with better PFS (62·6 vs. 4 months; P < 0·001) and longer OS (67·0 vs. 7·3 months; P < 0·001) compared to no CR. CD30 was expressed across all subtypes; >15% of cells were positive in anaplastic lymphoma kinase-positive and -negative anaplastic large-cell lymphoma and extranodal natural killer PTCL groups. We observed PTCL distribution across subtypes based on haematopathological re-evaluation. Poor prognosis, effect of specific prognostic indices, relevance of histopathological sub-classification, and response level to first-line treatment on outcomes were confirmed. Immune disorders amongst patients require further examination involving genetic studies and identification of associated immunosuppressive factors.

CCND2 and CCND3 hijack immunoglobulin light-chain enhancers in cyclin D1- mantle cell lymphoma.

Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation resulting in overexpression of cyclin D1. However, a small subset of cyclin D1- MCL has been recognized, and approximately one-half of them harbor CCND2 translocations while the primary event in cyclin D1-/D2- MCL remains elusive. To identify other potential mechanisms driving MCL pathogenesis, we investigated 56 cyclin D1-/SOX11+ MCL by fluorescence in situ hybridization (FISH), whole-genome/exome sequencing, and gene-expression and copy-number arrays. FISH with break-apart probes identified CCND2 rearrangements in 39 cases (70%) but not CCND3 rearrangements. We analyzed 3 of these negative cases by whole-genome/exome sequencing and identified IGK (n = 2) and IGL (n = 1) enhancer hijackings near CCND3 that were associated with cyclin D3 overexpression. By specific FISH probes, including the IGK enhancer region, we detected 10 additional cryptic IGK juxtapositions to CCND3 (6 cases) and CCND2 (4 cases) in MCL that overexpressed, respectively, these cyclins. A minor subset of 4 cyclin D1- MCL cases lacked cyclin D rearrangements and showed upregulation of CCNE1 and CCNE2. These cases had blastoid morphology, high genomic complexity, and CDKN2A and RB1 deletions. Both genomic and gene-expression profiles of cyclin D1- MCL cases were indistinguishable from cyclin D1+ MCL. In conclusion, virtually all cyclin D1- MCLs carry CCND2/CCND3 rearrangements with immunoglobulin genes, including a novel IGK/L enhancer hijacking mechanism. A subset of cyclin D1-/D2-/D3- MCL with aggressive features has cyclin E dysregulation. Specific FISH probes may allow the molecular identification and diagnosis of cyclin D1- MCL.

Cytokeratin expression in plasmablastic lymphoma - a possible diagnostic pitfall in the routine work-up of tumours.

AIMS: Plasmablastic lymphoma (PBL) is a rare aggressive B-cell lymphoma that frequently arises at extranodal sites in the setting of immunosuppression. The diagnosis of PBL is complex, owing to a frequent solid or cohesive growth pattern, and an often unusual immunophenotype. Several case reports have described cytokeratin (CK) expression in PBL, introducing a diagnostic pitfall. The aim of this study was to determine the frequency of CK expression in PBL in the largest series available to date. METHODS AND RESULTS: By using immunohistochemistry in a cohort of 72 PBLs, we identified CK8/18 positivity in 11 of 72 cases (15%) and AE1/3 positivity in six of 65 cases (9%), clearly contrasting with a control series of non-PBL aggressive B-cell lymphomas (one of 96 diffuse large B-cell lymphomas), as well as with data in the literature describing only occasional CK expression in haematological neoplasms. CONCLUSIONS: Our data indicate CK expression in a substantial number (15%) of PBLs. In view of the particular morphological features of PBL and its frequent negativity for the common leukocyte antigen and B-cell markers, this feature represents a pitfall in the routine diagnostic work-up of PBL, and requires more extensive immunohistochemical and molecular characterisation of cases entering the differential diagnosis.

Long-term outcome comparing histological grades of follicular lymphoma patients treated with immunochemotherapy as first-line therapy: A retrospective analysis from two institutions.

OBJECTIVES: To clarify the impact of histological grades in follicular lymphoma. METHODS: We retrospectively analysed 250 patients diagnosed with FL treated with chemoimmunotherapy: 188 patients were grades 1-2 and 62 grade 3A. RESULTS: In our series, grade 3A FL patients were older, higher proportion of localised disease and lower bone marrow infiltration at diagnosis comparing grades 1-2 FL patients. Estimated six-year progression-free survival and time to progression showed no differences between both groups [grade 3A: 56% (95%CI: 39%-73%) and 51% (95%CI: 41%-61%) vs grades 1-2:55% (95%CI: 46%-63%) and 57% (95%CI: 49%-65%), P = .782 and P = .521, respectively]. Estimated six-year overall survival was lower, 76% (95%CI: 64%-88%) for the grade 3A group than grades 1-2 83% (95%CI: 77%-89%); P = .044. In addition to that, cumulative incidence curves of death not related to lymphoma at 10 years between groups were as follows: [0.26 (95%CI: 0.25-0.27) and 0.05 (95%CI: 0.04-0.06) for G3AFL and G1-2FL, respectively], P = .010. Grade 3A FL showed in PFS curve no relapses after 6 years. These results were absolutely reproduced in 199 patients receiving R-CHOP regimen as induction. CONCLUSIONS: Our results indicate similar long-term outcomes in terms of progression-free survival and time to progression in grades 1-2 and 3A. No relapses were observed in G3AFL group after 6 years.

Clinicopathologic features and prognostic significance of CD30 expression in de novo diffuse large B-cell lymphoma (DLBCL): results in a homogeneous series from a single institution.

Introduction: The present study evaluates CD30 expression by immunohistochemistry (IHQ) in 216 patients with de novo DLBCL.Methods: CD30 expression was assessed retrospectively in all cases by IHQ. More than >0% and >20% of CD30 expression in the malignant cells were used as a cut-off for positivity. Survival was analysed in 176 patients treated with R-CHOP/R-CHOP-like regimens.Results: CD30 expression >0% was found in 66 (31%) patients, and >20% in 41 (19%). Younger patients <60 years (p = 0.03), good performance status (p = 0.04), and non-GCB subtype (p = 0.004) correlated with CD30 expression. No significant differences were found in overall survival and progression-free survival (PFS), although there was a trend towards better PFS in CD30-positive patients (p = 0.07). Among 7 patients with Epstein-Barr virus (EBV)-positive-DLBCL, CD30 was expressed in 71%, and 2-year PFS significantly inferior compared with CD30-positive EBV-negative-DLBCL patients (p = 0.01).Conclusion: CD30 is expressed in 30% of DLBCL patients, in whom targeted therapy with an anti-CD30 monoclonal antibody could be explored. CD30 is expressed more frequently younger patients, with better performance status and in the non-GCB subtype and its expression trends towards a better PFS. No significant differences regarding characteristics at diagnosis or prognosis were found between groups with different cut-off for positivity.

Clinicopathological evaluation of the programmed cell death 1 (PD1)/programmed cell death-ligand 1 (PD-L1) axis in post-transplant lymphoproliferative disorders: association with Epstein-Barr virus, PD-L1 copy number alterations, and outcome.

AIMS: The clinical implications of the programmed cell death 1 (PD1)/programmed cell death-ligand 1 (PD-L1) axis in patients with post-transplant lymphoproliferative disorders are largely unknown, and its association with Epstein-Barr virus (EBV) status and PD-L1 copy number alterations (CNAs) has not been thoroughly studied. METHODS AND RESULTS: PD1/PD-L1 expression was studied in 50 adult post-transplant lymphoproliferative disorders, and the correlations with PD-L1 CNAs, EBV, clinicopathological features and outcome were evaluated. Thirty-seven (74%) cases were classified as diffuse large B-cell lymphoma (DLBCL), nine (18%) cases were classified as polymorphic, and four (8%) cases were classified as classic Hodgkin lymphoma. Thirty-four cases were EBV-positive, with 29 of 34 (85%) having latency II or III, and 15 of 34 (44%) having viral replication. PD-L1 expression in tumour cells and tumour-associated macrophages was observed in 30 (60%) and 37 (74%) cases, respectively. PD1 positivity was seen in 16 (32%) cases. PD-L1 expression was associated with EBV with latency II or III (P = 0.001) and organ rejection (P = 0.04), and, in DLBCL, with non-germinal centre type DLBCL (P < 0.001). Cases with PD-L1-positive tumour cells showed a higher number of PD-L1 CNAs than PD-L1-negative cases (P = 0.001). Patients with EBV/latency III/replication and simultaneous PD-L1 expression showed the worst overall survival (P < 0.001). CONCLUSIONS: The PD1/PD-L1 axis is deregulated in post-transplant lymphoproliferative disorders, with frequent PD-L1 expression and PD1 negativity. PD-L1 expression is associated with EBV latency II or III and PD-L1 CNAs, and probably reflects a proinflammatory tumour microenvironment. The combined analysis of EBV status and PD-L1 expression may help to identify deeply immunosuppressed patients who can benefit from immune reconstitution approaches.

Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma.

Constitutive activation of the chemokine receptor CXCR4 has been associated with tumor progression, invasion, and chemotherapy resistance in different cancer subtypes. Although the CXCR4 pathway has recently been suggested as an adverse prognostic marker in diffuse large B-cell lymphoma, its biological relevance in this disease remains underexplored. In a homogeneous set of 52 biopsies from patients, an antibody-based cytokine array showed that tissue levels of CXCL12 correlated with high microvessel density and bone marrow involvement at diagnosis, supporting a role for the CXCL12-CXCR4 axis in disease progression. We then identified the tetra-amine IQS-01.01RS as a potent inverse agonist of the receptor, preventing CXCL12-mediated chemotaxis and triggering apoptosis in a panel of 18 cell lines and primary cultures, with superior mobilizing properties in vivo than those of the standard agent. IQS-01.01RS activity was associated with downregulation of p-AKT, p-ERK1/2 and destabilization of MYC, allowing a synergistic interaction with the bromodomain and extra-terminal domain inhibitor, CPI203. In a xenotransplant model of diffuse large B-cell lymphoma, the combination of IQS-01.01RS and CPI203 decreased tumor burden through MYC and p-AKT downregulation, and enhanced the induction of apoptosis. Thus, our results point out an emerging role of CXCL12-CXCR4 in the pathogenesis of diffuse large B-cell lymphoma and support the simultaneous targeting of CXCR4 and bromodomain proteins as a promising, rationale-based strategy for the treatment of this disease.

m7FLIPI and targeted sequencing in high-risk follicular lymphoma.

Patients with follicular lymphoma (FL) refractory to front-line immunochemotherapy (ICT) have a poor overall survival (OS). Gene mutation analysis may be more accurate than classical risk factors to pick out these patients before treatment. This study aimed to describe the prevalence of selected genetic mutations in a cohort of patients with high-risk FL. Twenty-five patients with FL refractory to front-line ICT and 10 non-refractory patients matched for age, sex, and FLIPI score were included. We sequenced 18 genes (custom targeted sequencing panel) previously reported to potentially have prognostic impact, including the seven genes necessary to determine m7FLIPI risk. The 35 patients had a median age of 62. The FLIPI and FLIPI2 were high in 27 (84%) and 14 (48%), respectively. Three-year progression-free survival (PFS) and OS probabilities were 25% (95% CI, 13%-41%) and 53% (34%-69%), respectively. There were 73 variants in the 18 genes among the 35 patients. The median number of mutations per patient was 1 (interquartile range, 0-3). The most commonly mutated genes were CREBBP (11 of 35, 31%) and EP300 (10 of 35, 29%). EP300 mutations were associated with refractoriness to treatment (10 of 25 among refractory and 0 of 10 among non-refractory). In conclusion, in this study, patients with high-risk follicular lymphoma were genetically heterogeneous.

Primary cutaneous vs secondary cutaneous follicular lymphomas: A comparative study focused on BCL2, CD10, and t(14;18) expression.

BACKGROUND: Primary cutaneous follicular center-cell lymphoma (PCFCL) is one of the most common types of cutaneous B-cell lymphoma. Differences in immunohistochemical expression of BCL2 and CD10 antigens along with the presence of t(14:18) translocation in neoplastic cells have been postulated as relevant clues in differentiating PCFCL from cutaneous lesions secondary to a systemic follicular lymphoma (SCFL). The aim of this study is to evaluate the significance and usefulness of these parameters in a large series of patients. METHODS: Patients with PCFCL and SCFL diagnosed at three university hospitals in Barcelona, from 2000 to 2015 were reviewed. Clinical, histopathological, immunophenotypical, genetic, and outcome parameters were analyzed. RESULTS: Eighty-one cases (59 PCFCL and 22 SCFL) were included. There were no significant differences between PCFCL and SCFL cases regarding clinical presentation, site of involvement, or predominant type of skin lesions. Most patients in both groups showed positivity for BCL2 and CD10, but strong expression of BCL2 and CD10 was associated with SCFL cases. Although more frequent in SCFL, a small proportion of PCFCL cases also showed the t(14:18) on FISH analysis. CONCLUSION: The intensity of BCL2 expression was found to be the single most valuable clue in differentiating PCFCL from SCFL cases on histopathological grounds.

Study of breast cancer incidence in patients of lymphangioleiomyomatosis.

Molecular evidence has linked the pathophysiology of lymphangioleiomyomatosis (LAM) to that of metastatic breast cancer. Following on this observation, we assessed the association between LAM and subsequent breast cancer. An epidemiological study was carried out using three LAM country cohorts, from Japan, Spain, and the United Kingdom. The number of incident breast cancer cases observed in these cohorts was compared with the number expected on the basis of the country-specific incidence rates for the period 2000-2014. Immunohistochemical studies and exome sequence analysis were performed in two and one tumors, respectively. All cohorts revealed breast cancer standardized incidence ratios (SIRs) ≥ 2.25. The combined analysis of all cases or restricted to pre-menopausal age groups revealed significantly higher incidence of breast cancer: SIR = 2.81, 95 % confidence interval (CI) = 1.32-5.57, P = 0.009; and SIR = 4.88, 95 % CI = 2.29-9.99, P = 0.0007, respectively. Immunohistochemical analyses showed positivity for known markers of lung metastatic potential. This study suggests the existence of increased breast cancer risk among LAM patients. Prospective studies may be warranted to corroborate this result, which may be particularly relevant for pre-menopausal women with LAM.

Small-cell predominant extranodal NK/T cell lymphoma, nasal type: clinicopathological analysis of a series of cases diagnosed in a Western population.

AIMS: Extranodal NK/T cell lymphoma, nasal type (ENKTCL) is usually composed of medium- to large-sized lymphoid cells showing prominent angiotrophism and tumour cell necrosis. We report 13 cases composed predominantly of small lymphocytes diagnosed in the United States and Western Europe. METHODS AND RESULTS: Patients included seven females and six males aged 17-75 years. Ten presented with sinonasal and three with buccal disease. Nine had stage IE/IIE and four had stage IV disease. In five of seven patients with multiple biopsies at different time-intervals, the lymphoma was misinterpreted as representing chronic inflammation on an earlier biopsy. In all cases morphology showed a dense infiltrate of small lymphoid cells with minimal cytological atypia. Necrosis, angioinvasion and angiodestruction were each seen in 17%, 22% and 17% of biopsies. Median Ki67 was 5%. Four patients died of lymphoma 4-16 months after diagnosis, including three of four patients with stage IV disease; seven (54%) are alive with no evidence of disease at a median of 39 months; one patient with stage IV disease is alive at 10 months and one recurred at 17 months. CONCLUSIONS: In sinonasal biopsies with predominantly small lymphocytic infiltrates with admixed chronic inflammation, focal hypercellularity, focal surface ulceration or microscopic bone invasion by small lymphoid cells should alert pathologists to the possibility of small-cell predominant ENKTCL. Awareness of the full histological spectrum of ENKTCL, particularly in non-endemic areas, is important in avoiding a delay in diagnosis and ensuring timely initiation of therapy.

CD 30-positive transformed follicular lymphoma: two case reports and literature review.

AIMS: Here we report two cases of follicular lymphoma that transformed to CD30 positive diffuse large B cell lymphoma and review the literature on this topic. RESULTS: The first case represents an example of early transformation of conventional low-grade follicular lymphoma to CD30-positive large B cell lymphoma. Immunoglobulin (Ig)H and cytogenetic identity was demonstrated between both components. High-dose and auto-stem cell transplant (SCT) was applied and complete response was achieved. The second case represents an example of d'emblee transformation of intrafollicular neoplasia to CD30-positive large B cell lymphoma. Immunoglobulin K deleting element (IgKde) and cytogenetic identity between both phases was demonstrated. The patient was in partial response after four cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). CONCLUSIONS: CD30 expression was found to be associated in these cases to the transformation event and could be considered a therapeutic target to add to conventional immunochemotherapeutic regimens, even in combination with auto-SCT. We suggest looking for CD30 expression in transformed follicular lymphoma cases.