Post-diagnostic statin use and breast cancer-specific mortality: a population-based cohort study.

PURPOSE: Statins are the most widely prescribed cholesterol lowering medications and have been associated with both improved and unchanged breast cancer outcomes in previous studies. This study examines the association between the post-diagnostic use of statins and breast cancer outcomes (death and recurrence) in a large, representative sample of New Zealand (NZ) women with breast cancer. METHODS: Women diagnosed with a first primary breast cancer between 2007 and 2016 were identified from four population-based regional NZ breast cancer registries and linked to national pharmaceutical data, hospital discharges, and death records. Cox proportional hazard models were used to estimate the hazard of breast cancer-specific death (BCD) associated with any post-diagnostic statin use. RESULTS: Of the 14,976 women included in analyses, 27% used a statin after diagnosis and the median follow up time was 4.51 years. Statin use (vs non-use) was associated with a statistically significant decreased risk of BCD (adjusted hazard ratio: 0.74; 0.63-0.86). The association was attenuated when considering a subgroup of 'new' statin users (HR: 0.91; 0.69-1.19), however other analyses revealed that the protective effect of statins was more pronounced in estrogen receptor positive patients (HR: 0.77; 0.63-0.94), postmenopausal women (HR: 0.74; 0.63-0.88), and in women with advanced stage disease (HR: 0.65; 0.49-0.84). CONCLUSION: In this study, statin use was associated with a statistically significant decreased risk of breast cancer death, with subgroup analyses revealing a more protective effect in ER+ patients, postmenopausal women, and in women with advanced stage disease. Further research is warranted to determine if these associations are replicated in other clinical settings.

Trends in incidence, therapy and outcome of localized nodal and extranodal marginal zone lymphomas: declining incidence and inferior outcome for gastrointestinal sites.

Population-based series analyzing clinical implications of nodal versus extranodal presentation of marginal zone lymphoma (MZL) are lacking. We studied clinical differences and trends in incidence, therapy and survival of nodal and extranodal MZL, and of MZL at different extranodal sites, in a population-based cohort. All patients with localized (Ann Arbor stage I and II) nodal (n = 211), splenic (n = 54) and extranodal (n = 1449) MZL, diagnosed between 1994 and 2010, were selected from The Netherlands Cancer Registry. Between 1994 and 2010 the incidence of nodal and extranodal MZL increased. The incidence of gastric MZL decreased. Patients with nodal MZL received more chemotherapy and targeted therapies than their extranodal counterparts. A trend in time toward less chemotherapy and more irradiation was observed. Overall survival (OS) curves for nodal and extranodal MZL overlapped (5-year OS 76% and 77%, respectively). Patients with a primary gastrointestinal (GI) localization had inferior OS compared to patients with non-GI extranodal MZL (5-year OS 71% and 85%, p < 0.0001). Patients with localized extranodal MZL presented more commonly with stage I disease, but their clinical presentation and survival were otherwise similar to patients with localized nodal MZL. MZL arising in the GI tract does not have a good prognosis and requires a different treatment approach.

Undertreatment of patients with localized extranodal compared with nodal diffuse large B-cell lymphoma.

Population-based studies analyzing clinical implications of nodal versus extranodal (EN) presentation of diffuse large B-cell lymphoma (DLBCL) are scarce. We studied clinical differences and trends in incidence, treatment and survival of nodal and EN DLBCL in a population-based cohort. All patients newly diagnosed with localized (Ann Arbor stage [AAS] I and II) nodal (n = 5124) and EN (n = 4776) DLBCL, and primary mediastinal B-cell lymphoma (PMBL; n = 88), diagnosed between 1989 and 2010, were selected from the Netherlands Cancer Registry. Primary EN disease was correlated with older age and more favorable clinical stage (AAS I). The age standardized incidence rates for men with localized EN DLBCL, and for men and women with localized PMBL, increased significantly, whereas the age standardized incidence rates of all other subgroups remained stable. The stomach was the most common EN localization. Patients with EN disease received less chemotherapy and targeted therapy than their nodal counterparts, irrespective of age and period of diagnosis. Their 5-year overall survival (OS) was 48% vs. 54% in the nodal group, but in multivariate analysis primary extranodal presentation was not independently associated with inferior survival. This population-based study shows clinically relevant differences between localized nodal and EN DLBCL and PMBL. Since patients with EN were significantly less often optimally treated, we advocate better interaction between medical disciplines.

T(14;18)(q32;q21) involving MALT1 and IGH genes occurs in extranodal diffuse large B-cell lymphomas of the breast and testis.

Primary B-cell lymphoma of the testis, breast and thyroid are rare and data concerning cytogenetic aberrations at these extranodal sites are scarce. We examined the presence of extranodal marginal zone lymphoma-associated translocations, t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), t(3;14)(p14.1;q32) and numerical aberrations of chromosomes 1, 3, 12 and 18 by fluorescence in situ hybridization in 6 extranodal marginal zone lymphomas and 24 diffuse large B-cell lymphomas with (n=9) or without (n=15) marginal zone lymphoma components, with primary localizations in the breast (n=15), testis (n=9) and thyroid (n=6). We found t(14;18)(q32;q21), with breakpoints in IGH and MALT1, in one testicular diffuse large B-cell lymphoma and in two diffuse large B-cell lymphomas of the breast. No other translocations, amplifications or deletions involving IGH, BCL-10, BCL-2, MALT1 and IAP2 were detected. Numerical aberrations occurred in 67% of the lymphomas, 67% of extranodal marginal zone lymphomas, 56% of diffuse large B-cell lymphomas with marginal zone lymphoma components and in 73% of 'de novo' diffuse large B-cell lymphomas. These included 78% of testis, 67% of thyroid and 60% of breast lymphomas, and included mainly trisomy 18 (n=16), trisomy 3 (n=8) and trisomy 1 (n=3). One testicular diffuse large B-cell lymphoma harbored both t(14;18)(q32;q21) and trisomy 3. Our results indicate that at least a few cases of diffuse large B-cell lymphoma of the testis and the breast belong to the spectrum of extranodal marginal zone lymphoma.

Molecular pathogenesis and histologic and clinical features of extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue type.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) type (EMZL) is considered an antigen driven lymphoid malignancy associated with protracted antigenic stimulation by microbial pathogens, auto-antigens or other unknown stimuli, which trigger a sustained lymphoid proliferation at sites normally devoid of lymphoid tissue. With the progression of disease, chromosomal aberrations may occur. They result in aberrant activation of signaling pathways which lead to the lymphoproliferation becoming independent of antigenic stimulation. The nuclear factor κB (NF-κB) pathway plays a central role in the lymphomagenesis of EMZL. Four mutually exclusive chromosomal translocations have been identified that lead to the up-regulation of either BCL10 or MALT1 or the generation of a fusion protein, cIAP2-MALT1, and induce aberrant activation of the NF-κB pathway. In translocation-negative EMZL, inactivation of the global NF-κB inhibitor A20 might play an important role. These genetic abnormalities alone are insufficient for malignant transformation. Other factors, such as cell surface and chemokine receptors and factors involved with immune and inflammatory response, play their own unique role in the development of a malignant EMZL and may determine its unique clinico-pathological presentation. This review provides an overview of the histologic and clinical features of EMZL and discusses the current insights into the molecular mechanisms underlying the development of EMZL.

Clinical and pathological features of testicular diffuse large B-cell lymphoma: a heterogeneous disease.

Most testicular lymphomas are of diffuse large B-cell (DLBCL) type with an outcome inferior to nodal DLBCL. Within an apparently homogeneous group of testicular DLBCLs, small cell components, plasmacytoid differentiation and lymphoepithelial lesions (LELs), features of extranodal marginal zone lymphoma (eMZL), can be identified. The aim of this study was to define the histological features of testicular DLBCL and correlate this with their clinical behavior and outcome. Thirty-six patients with testicular DLBCL (Ann Arbor stage I/II) were identified through the databases of two Dutch regional cancer registries, diagnosed between 1981 and 1999. Follow-up for patients alive was more than 10 years. Medical records and pathology specimens were reviewed. eMZL features were found in 53% of the cases of localized stage testicular DLBCL. Compared to patients with "pure" DLBCL, patients with DLBCL with eMZL features presented more often with stage I disease, normal lactate dehydrogenase, smaller tumors and absence of B-symptoms, and they responded more favorably to initial treatment. Their median survival was 48 months versus 12 months for "pure" DLBCL (p = 0.87). Features of eMZL were commonly identified in testicular DLBCL and they correlated with a more favorable clinical presentation and better response to initial therapy. However, these differences did not reach statistical significance due to small numbers.

Treatment and survival of patients with thyroid lymphoma: a population-based study with clinical and pathologic reviews.

PURPOSE: The purpose of this study was to determine the incidence, clinical and histologic features, and patterns of outcome of thyroid lymphomas. PATIENTS AND METHODS: A retrospective population-based survey of 38 patients with thyroid lymphoma was taken. Median age was 69 years (range, 33-87 years), with a 1:4 female predominance. Fifty percent of cases had a history of autoimmune thyroiditis, and coexistent thyroiditis was found in 67% of cases in which preexistent thyroid tissue was present. The most common subtype was diffuse large B-cell lymphoma (DLBCL; 63%) followed by extranodal marginal zone lymphoma (ENMZL; 29%). Ten of the patients with DLBCL showed a concomitant low-grade mucosa-associated lymphatic tissue component, and 4 cases of aggressive ENMZL were diagnosed. At diagnosis, 22 patients (58%) had localized disease, and 41% had low-risk international prognostic index scores. RESULTS: Therapy was diverse and included all possible treatment modalities, none of which showed superiority. A complete clinical response was exhibited in 64% of patients, 14% exhibited a partial response, and 22% developed progressive disease. At a median follow-up of 43 months (range, 0-240 months), 15 patients had relapsed or developed progressive disease. Two-year overall survival rate was 59% for all patients, 68% for patients with localized disease, and 47% for patients with disseminated lymphoma. CONCLUSION: Many thyroid lymphomas have clinical and histologic features characteristic of ENMZL and belong to this specific clinicopathologic entity.