Purpose Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin lymphoma confined to the CNS. Whether there is a PCNSL-specific genomic signature and, if so, how it differs from systemic diffuse large B-cell lymphoma (DLBCL) is uncertain. Experimental design We performed a comprehensive genomic study of tumor samples from 19 immunocompetent PCNSL patients. Testing comprised array-comparative genomic hybridization and whole exome sequencing. Results Biallelic inactivation of TOX and PRKCD were recurrently found in PCNSL but not in systemic DLBCL, suggesting a specific role in PCNSL pathogenesis. Additionally, we found a high prevalence of MYD88 mutations (79%) and CDKN2A biallelic loss (60%). Several genes recurrently affected in PCNSL were common with systemic DLBCL, including loss of TNFAIP3, PRDM1, GNA13, TMEM30A, TBL1XR1, B2M, CD58, activating mutations of CD79B, CARD11 and translocations IgH-BCL6. Overall, BCR/TLR/NF-κB pathways were altered in >90% of PNCSL, highlighting its value for targeted therapeutic approaches. Furthermore, integrated analysis showed enrichment of pathways associated with immune response, proliferation, apoptosis, and lymphocyte differentiation. Conclusions In summary, genome-wide analysis uncovered novel recurrent alterations, including TOX and PRKCD, helping to differentiate PCNSL from systemic DLBCL and related lymphomas.

Lymphoplasmacytic lymphoma involving the bone marrow can be difficult to diagnose, and pathological features that predict the presence of associated Waldenströ m's macroglobulinemia have yet to be identified. To address these issues, marrow histology, immunohistochemistry, and flow cytometry were studied from 35 lymphoplasmacytic lymphoma cases that had comprehensive clinical assessment for Waldenströ m's macroglobulinemia. In all cases, the plasma cells were analyzed by a novel 6-color flow method. Both immunohistochemistry and flow cytometry were useful in identifying the lymphoid and plasmacytic disease components. In 19 cases, immunohistochemistry revealed an earlier unrecognized pattern of plasma cell infiltration in which they were physically separate from the lymphoid infiltrates. B-cell flow cytometry revealed monotypic cells in 96% of the cases. Approximately half of these were CD5 and/or CD23 positive, although none had features of chronic lymphocytic leukemia, and none of the B cells had flow cytometric features suggesting plasmacytic differentiation. In contrast, highly sensitive 6-color plasma cell flow cytometry revealed monotypic cells in 32 of the 35 cases; in 20 cases, the pattern of CD38 and CD138 coexpression detected was identical to that seen in plasma cell malignancies such as multiple myeloma. In 18 of these 20 lymphoplasmacytic lymphoma cases, these plasma cells were CD19 positive, distinguishing them from those of true plasma cell neoplasms, which are CD19 negative. It is interesting that the two lymphoplasmacytic lymphoma cases with CD19-negative plasma cells had an IgG isotype serum paraprotein. Apart from this, no other pathological correlates of the clinical or laboratory features of symptomatic Waldenströ m's macroglobulinemia were identified.

Squamous cell carcinoma of the head and neck, particularly basaloid squamous cell carcinoma, may be difficult to distinguish from high-grade adenoid cystic carcinoma. Evidence of human papilloma virus (HPV) infection, particularly HPV 16, is frequently found in non-keratinizing oropharyngeal squamous cell carcinoma. Immunoreactivity for p16, a surrogate marker for HPV infection, often parallels the HPV infection status in oropharyngeal squamous cell carcinoma. However, the incidence and correlation between p16 expression and HPV infection in high-grade adenoid cystic carcinoma is unknown. Sixteen cases of high-grade adenoid cystic carcinoma, three cases of dedifferentiated adenoid cystic carcinoma and eight cases of low-/intermediate-grade adenoid cystic carcinoma were identified for inclusion in the study. All cases were tested by immunohistochemistry for p16 expression and in situ hybridization for high-and low-risk HPV. Eight cases (100%) of low-to-intermediate-grade adenoid cystic carcinoma were focally positive for p16, all of which were negative for HPV. In all, 14 of 16 cases (88%) of high-grade adenoid cystic carcinoma and three cases (100%) of dedifferentiated adenoid cystic carcinoma were positive for p16; strong and diffuse staining was noted in three cases (3 of 19, 16%). Two cases (11%) of high-grade adenoid cystic carcinoma, which were also diffusely positive for p16, showed the presence of high-risk HPV. These findings suggest that the presence of HPV infection in high-grade adenoid cystic carcinoma is infrequent, even in the presence of p16 immunostaining. Nevertheless, HPV positivity should not be used to exclude the possibility of high-grade adenoid cystic carcinoma when the differential diagnosis includes squamous cell carcinoma. Moreover, although p16 overexpression is often used as a surrogate marker for HPV in squamous cell carcinoma, it cannot be used in this manner in high-grade adenoid cystic carcinoma.

Systemic anaplastic large cell lymphomas (ALCLs) are classified into ALK-positive and ALK-negative types. We recently reported that ALK-negative ALCLs are genetically heterogenous. The largest subset, representing 30% of cases, had rearrangements of the DUSP22 locus. These cases had favorable outcomes similar to ALK-positive ALCL, and superior to other ALK-negative ALCLs. Here, we examined the morphologic features of these cases in more detail. First, we conducted blinded review of hematoxylin and eosin slides of 108 ALCLs from our previous study, scoring cases for the presence of 3 histologic patterns and 5 cell types. Cases then were unblinded and re-reviewed to understand these features further. DUSP22-rearranged ALCLs were more likely than other ALK-negative ALCLs to have so-called doughnut cells (23% vs. 5%; P = 0.039), less likely to have pleomorphic cells (23% vs. 49%; P = 0.042), and nearly always (95%) had areas with sheet-like growth (common pattern). To examine the reproducibility of these findings, we conducted blinded review of hematoxylin and eosin slides of 46 additional ALK-negative ALCLs using a 0 to 3 scoring system to predict likelihood of DUSP22 rearrangement, the results of which correlated strongly with subsequent findings by fluorescence in situ hybridization (P < 0.0001). Although all ALCLs share certain morphologic features, ALCLs with DUSP22 rearrangements show significant differences from other ALK-negative ALCLs, typically showing sheets of hallmark cells with doughnut cells and few large pleomorphic cells. These morphologic findings and our previous outcome data suggest that ALK-positive ALCLs and DUSP22-rearranged ALCLs represent prototypical ALCLs, whereas ALCLs lacking rearrangements of both DUSP22 and ALK require further study.

Chromosomal translocations involving the MALT1 gene are hallmarks of mucosa-associated lymphoid tissue (MALT) lymphoma. To date, targeting these translocations to mouse B cells has failed to reproduce human disease. Here, we induced MALT1 expression in mouse Sca1 + Lin − hematopoietic stem/progenitor cells, which showed NF-κB activation and early lymphoid priming, being selectively skewed toward B-cell differentiation. These cells accumulated in extranodal tissues and gave rise to clonal tumors recapitulating the principal clinical, biological, and molecular genetic features of MALT lymphoma. Deletion of p53 gene accelerated tumor onset and induced transformation of MALT lymphoma to activated B-cell diffuse large-cell lymphoma (ABC-DLBCL). Treatment of MALT1-induced lymphomas with a specific inhibitor of MALT1 proteolytic activity decreased cell viability, indicating that endogenous Malt1 signaling was required for tumor cell survival. Our study shows that human-like lymphomas can be modeled in mice by targeting MALT1 expression to hematopoietic stem/progenitor cells, demonstrating the oncogenic role of MALT1 in lymphomagenesis. Furthermore, this work establishes a molecular link between MALT lymphoma and ABC-DLBCL, and provides mouse models to test MALT1 inhibitors. Finally, our results suggest that hematopoietic stem/progenitor cells may be involved in the pathogenesis of human mature B-cell lymphomas.