Purpose Breast implant–associated anaplastic large-cell lymphoma (ALCL) is a recently described clinicopathologic entity that usually presents as an effusion-associated fibrous capsule surrounding an implant. Less frequently, it presents as a mass. The natural history of this disease and long-term outcomes are unknown. Patients and Methods We reviewed the literature for all published cases of breast implant–associated ALCL from 1997 to December 2012 and contacted corresponding authors to update clinical follow-up. Results The median overall survival (OS) for 60 patients was 12 years (median follow-up, 2 years; range, 0-14 years). Capsulectomy and implant removal was performed on 56 of 60 patients (93%). Therapeutic data were available for 55 patients: 39 patients (78%) received systemic chemotherapy, and of the 16 patients (28%) who did not receive chemotherapy, 12 patients opted for watchful waiting and four patients received radiation therapy alone. Thirty-nine (93%) of 42 patients with disease confined by the fibrous capsule achieved complete remission, compared with complete remission in 13 (72%) of 18 patients with a tumor mass. Patients with a breast mass had worse OS and progression-free survival (PFS; P = .052 and P = .03, respectively). The OS or PFS were similar between patients who received and did not receive chemotherapy (P = .44 and P = .28, respectively). Conclusion Most patients with breast implant–associated ALCL who had disease confined within the fibrous capsule achieved complete remission. Proper management for these patients may be limited to capsulectomy and implant removal. Patients who present with a mass have a more aggressive clinical course that may be fatal, justifying cytotoxic chemotherapy in addition to removal of implants.

Human histocompatibility leukocyte antigen (HLA)-DO, a lysosomal resident major histocompatibility complex class II molecule expressed in B cells, has previously been shown to be a negative regulator of HLA-DM peptide loading function. We analyze the expression of DO in human peripheral blood, lymph node, tonsil, and bone marrow to determine if DO expression is modulated in the physiological setting. B cells, but not monocytes or monocyte-derived dendritic cells, are observed to express this protein. Preclearing experiments demonstrate that ∼50% of HLA-DM is bound to DO in peripheral blood B cells. HLA-DM and HLA-DR expression is demonstrated early in B cell development, beginning at the pro-B stage in adult human bone marrow. In contrast, DO expression is initiated only after B cell development is complete. In all situations, there is a striking correlation between intracellular DO expression and cell surface class II–associated invariant chain peptide expression, which suggests that DO substantially inhibits DM function in primary human B cells. We report that the expression of DO is markedly downmodulated in human germinal center B cells. Modulation of DO expression may provide a mechanism to regulate peptide loading activity and antigen presentation by B cells during the development of humoral immune responses.

We determined the prevalence and significance of finding B cells without surface immunoglobulin (SIg) light chain expression. The flow cytometry database at Johns Hopkins Medical Institutions was searched for cases in which immunoglobulin light chain staining was performed to rule out a B-cell malignant neoplasm between January 1994 and February 2000. We excluded plasma cell dyscrasias, precursor B-cell acute lymphoblastic leukemia/lymphomas, and hematogones. Cases with more than 25% of B cells lacking SIg light chain expression were retrieved. Polymerase chain reaction assays for immunoglobulin heavy chain gene rearrangements were performed in SIg-negative cases with available tissue blocks. We identified 36 cases; all represented lymphoma. Their diagnoses included diffuse large B-cell lymphoma (20), HIV-related lymphoma (5), follicular lymphoma (5), Burkitt lymphoma (2), monomorphic posttransplant lymphoproliferative disorder (1), chronic lymphocytic leukemia/small lymphocytic lymphoma (1), marginal zone B-cell lymphoma (1), and low grade B-cell lymphoma (1). Of the 17 SIg-negative cases with amplifiable DNAs, 12 (71%) showed a clonal immunoglobulin heavy chain gene rearrangement. SIg-negative B-cell lymphomas are rare. Complete absence of SIg light chain expression in a mature B cell proliferation can be used as a surrogate marker to help diagnose peripheral B-cell lymphoma.

We studied the antigen expression profiles of 19 anaplastic large cell lymphoma (ALCL) cases by multiparameter flow cytometry. The neoplastic cells expressed CD45, HLA-DR, and CD30 in all cases. At least 1 T cell-associated antigen was expressed in each case (CD2, 12/17 [71%]; CD4, 12/19 [63%]; CD3, 6/19 [32%]; CD7, 6/19 [32%]; CD5, 5/19 [26%]; CD8, 4/19 [21%]). CD25 was expressed in 14 (88%) of 16 cases. CD13 was expressed unexpectedly in 8 (47%) of 17 cases. One CD13+ ALCL also was positive for CD33 and 2 others for CD15, CD19, CD20, CD22, CD14, and CD36 were not expressed. Anaplastic lymphoma kinase protein was detected in about 33% (3/9) of ALCLs examined by flow cytometric immunophenotyping (FCI); expression was validated by immunohistochemical analysis. Of 19 ALCL cases, 12 were diagnosed solely based on FCI findings in conjunction with morphologic evaluation of body fluid (1 case), fine-needle aspirate (3 cases), or excisional biopsy specimen (8 cases). The diagnoses of the remaining 7 cases were suggested strongly by FCI and confirmed by immunohistochemical analysis. FCI is useful to aid in diagnosis of ALCL, particularly along with fine-needle aspiration evaluation. ALCL with aberrant expression of myeloid antigens should not be mistaken for extramedullary myeloid tumor.

MicroRNAome analyses have shown microRNA-630 (miR-630) to be involved in the regulation of apoptosis. However, its apoptotic role is still debated and its participation in DNA replication is unknown. Here, we demonstrate that miR-630 inhibits cell proliferation by targeting cell-cycle kinase 7 (CDC7) kinase, but maintains the apoptotic balance by targeting multiple activators of apoptosis under genotoxic stress. We identified a novel regulatory mechanism of CDC7 gene expression, in which miR-630 downregulated CDC7 expression by recognizing and binding to four binding sites in CDC7 3'-UTR. We found that miR-630 was highly expressed in A549 and NIH3T3 cells where CDC7 was downregulated, but lower in H1299, MCF7, MDA-MB-231, HeLa and 2BS cells where CDC7 was upregulated. Furthermore, the induction of miR-630 occurred commonly in a variety of human cancer and immortalized cells in response to genotoxic agents. Importantly, downregulation of CDC7 by miR-630 was associated with cisplatin (CIS)-induced inhibitory proliferation in A549 cells. Mechanistically, miR-630 exerted its inhibitory proliferation by blocking CDC7-mediated initiation of DNA synthesis and by inducing G1 arrest, but maintains apoptotic balance under CIS exposure. On the one hand, miR-630 promoted apoptosis by downregulation of CDC7; on the other hand, it reduced apoptosis by downregulating several apoptotic modulators such as PARP3, DDIT4, EP300 and EP300 downstream effector p53, thereby maintaining the apoptotic balance. Our data indicate that miR-630 has a bimodal role in the regulation of apoptosis in response to DNA damage. Our data also support the notion that a certain mRNA can be targeted by several miRNAs, and in particular an miRNA may target a set of mRNAs. These data afford a comprehensive view of microRNA-dependent control of gene expression in the regulation of apoptosis under genotoxic stress.

Posttransplant lymphoproliferative disorders (PTLDs) represent a spectrum ranging from Epstein-Barr virus (EBV)-driven polyclonal lymphoid proliferations to EBV+ or EBV- malignant lymphomas. Central nervous system (CNS) PTLDs have not been characterized fully. We reviewed the clinical, radiologic, and pathologic features of 12 primary CNS PTLDs to define them more precisely. Patients included 10 males and 2 females (median age, 43.4 years) who were recipients of kidney (n = 5), liver (n = 2), heart (n = 2), peripheral blood stem cells (n = 2), or bone marrow (n = 1). All received immunosuppressive therapy. CNS symptoms developed 3 to 131 months (mean, 31 months) after transplantation. By neuroimaging, most showed multiple (3 to 9) intra-axial, contrast-enhancing lesions. Histologic sections showed marked expansion of perivascular spaces by large, cytologically malignant lymphoid cells that were CD45+, CD20+, EBV+ and showed light chain restriction or immunoglobulin gene rearrangement. In distinction to PTLDs in other organ systems, CNS PTLDs were uniformly high-grade lymphomas that fulfilled the World Health Organization criteria for monomorphic PTLDs. Extremely short survival periods were noted for each CNS PTLD that followed peripheral blood stem cell transplantation. Survival of others with CNS PTLD varied; some lived more than 2 years.

In an attempt to amplify cervid satellite II DNA from the genomes of Indian muntjac and Chinese muntjac, a pair of primers derived from the white tailed deer satellite II DNA clone (OvDII) yielded a prominent 1 kb polymerase chain reaction (PCR) product (in addition to the expected 0.7 kb satellite II DNA fragments) in both species. The ~1 kb products were cloned, sequenced, and analyzed by Southern blotting and fluorescence in situ hybridization (FISH). This revealed that thẽ 1 kb cloned sequences indeed represent a previously unknown cervid satellite DNA family, which is now designated as cervid satellite IV DNA. Approximately 1 kb PCR clones were also obtained from the genomes of the black tailed deer and Canadian woodland caribou with similar primer pairs. Extremely high sequence conservation (over 90% homology) was observed among the clones generated from all four deer species and PCRSouthern hybridization experiments further verified the co-amplification of two kinds of satellite DNA sequences with the same pair of primers. This satellite DNA was found to co-localize with centromeric proteins at the kinetochore by a simultaneous FISH and immunofluorescence study. Due to its high sequence conservation and close association with kinetochores, the newly identified satellite DNA may have a functional centromeric role.

Using a cDNA microarray, we compared the expression of approximately 8000 genes between two unique, clonally related T cell lines derived from different stages of a progressive T cell lymphoma involving skin. A total of 180 genes was found to be differentially expressed at the RNA level by a factor of fivefold or greater. Cutaneous T cell lymphoma is the most common lymphoproliferative disorder involving skin. It usually is an indolent, low-grade tumor at the time of presentation. Over time, the CTCL often undergoes transformation to an aggressive, usually fatal high-grade large cell lymphoma.