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Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma usually are distinctly different in regard to clinical presentation, morphology, immunophenotype, and molecular/genetic findings. In spite of this, select cases may show overlapping characteristics and represent a diagnostic challenge. Cyclin D1 immunohistochemical staining is usually envisioned as a definitive method for resolving this differential diagnosis, with positivity supporting a diagnosis of mantle cell lymphoma. We report a case involving a 58-year-old man with a diagnosis of CLL/SLL for several years. A lymph node excision was performed after increased adenopathy was noted in the cervical region. The excised lymph node showed typical morphologic findings of CLL/SLL, including the presence of characteristic proliferation centers. Cyclin D1 staining, using 3 different antibodies, was present in scattered prolymphocytes and paraimmunoblasts, mostly within proliferation centers. Fluorescence in situ hybridization and conventional cytogenetics demonstrated trisomy 12 and an absence of t(11 ;14) in lymph node tissue. Focal cyclin D1 expression by immunohistochemistry in nodal CLL/SLL is quite unusual and is discussed as a potential diagnostic pitfall. [ABSTRACT FROM AUTHOR]

We report a case of an intraocular inflammatory myofibroblastic tumor nearly filling the vitreous cavity of the eye of a 50-year-old man. The tumor was composed of a mixture of spindle cells and mixed inflammatory elements, including numerous plasma cells. The differential diagnosis included inflammatory pseudotumor and neoplastic mimics of this condition. Further investigation with immunohistochemistry revealed the mass to be composed of myofibroblasts, positive for smooth muscle actin stains and with weak anaplastic lymphoma kinase (ALK) expression in some tumor cells. Evaluation by fluorescence in situ hybridization revealed the tumor cells to have multiple copies of chromosome 2 and ALK but no rearrangement of the ALK gene. The authors propose that multiple copies of the ALK gene may be involved in inflammatory myofibroblastic tumor tumorigenesis, in addition to ALK gene rearrangements. [ABSTRACT FROM AUTHOR]

The diagnosis of classic Hodgkin lymphoma (CHL) in clinical practice remains reliant on tissue morphological and immunohistochemical evaluation. In this article, we illustrate specific scenarios that we have encountered in our clinical practice pertaining to diagnostic challenges in CHL. We begin with select presentations of morphologic variants of CHL and then discuss certain immunophenotypic deviations from what is deemed "normal patterns" of antigen expression by HRS cells. Lastly, we discuss mimickers of HRS cells, in lymphomatous and non-lymphomatous conditions., Competing Interests: Declaration of competing interest None of the authors declares conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

IGH::CCND1 translocation has been implicated as a preliminary finding in mantle cell lymphoma (MCL) and plasma cell myeloma, with cyclin D1 over-expression by immunohistochemistry stain, without gene rearrangement, reported in other hematologic neoplasms. CCND1 rearrangement has been reported infrequently as a secondary event in high-grade B-cell lymphomas. We present the case of an elderly man who was found to have a splenic marginal zone lymphoma with a heterozygous TP53 deletion. Years later at the time of relapse, the patient acquired a CCND1 rearrangement, in addition to a persistent TP53 deletion. Sequencing of the two lymphomas demonstrated clonal relatedness of the two processes. To our knowledge, this is the first report of a splenic marginal zone lymphoma with a TP53 deletion at diagnosis, evolving into a large B-cell lymphoma with a CCND1 rearrangement., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: The authors declare no conflict of interest.

We have designed and developed novel and selective TLR7 agonists that exhibited potent receptor activity in a cell-based reporter assay. In vitro , these agonists significantly induced secretion of cytokines IL-6, IL-1β, IL-10, TNFa, IFNa, and IP-10 in human and mouse whole blood. Pharmacokinetic and pharmacodynamic studies in mice showed a significant secretion of IFNα and TNFα cytokines. When combined with aPD1 in a CT-26 tumor model, the lead compound showed strong synergistic antitumor activity with complete tumor regression in 8/10 mice dosed using the intravenous route. Structure-activity relationship studies enabled by structure-based designs of TLR7 agonists are disclosed., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Enhancer of zeste homolog 2 (EZH2) is a catalytic component of the polycomb repressive complex 2 (PRC2) which reduces gene expression via trimethylation of a lysine residue of histone 3 (H3K27me3). Expression of EZH2 has not been assessed systematically in mantle cell lymphoma (MCL). Expression of EZH2 was assessed by immunohistochemistry in 166 patients with MCL. We also assessed other PRC2 components and H3K27me3. Fifty-seven (38%) of MCL patients were positive for EZH2 using 40% cutoff. EZH2 expression was associated with aggressive histologic variants (65% vs. 29%, p < 0.001), high Ki-67 proliferation rate (median, 72% vs. 19%, p < 0.001), and p53 overexpression (43% vs. 2%, p < 0.001). EZH2 expression did not correlate with expression of other PRC2 components (EED and SUZ12), H3K27me3, MHC-I, and MHC-II. Patients with EZH2 expression (EZH2+) had a poorer overall survival (OS) compared with patients without EZH2 expression (EZH2-) (median OS: 3.9 years versus 9.4 years, respectively, p < 0.001). EZH2 expression also predicted a poorer prognosis in MCL patients with classic histology (median OS, 4.6 years for EZH2+ and 9.6 years for EZH2-negative, respectively, p < 0.001) as well as aggressive histology (median OS, 3.7 years for EZH2+ and 7.9 years for EZH2-negative, respectively, p = 0.046). However, EZH2 expression did not independently correlate with overall survival in a multivariate analysis. Gene expression analysis and pathway enrichment analysis demonstrated a significant enrichment in cell cycle and mitotic transition pathways in MCL with EZH2 expression. EZH2 expression detected by immunohistochemistry is present in 38% of MCL cases and it is associated with high proliferation rate, p53 overexpression, aggressive histologic variants, and poorer OS. Based on gene expression profiling data, EZH2 expression could potentiate cell cycle machinery in MCL. These data suggest that assessment of EZH2 expression could be useful to stratify MCL patients into low- and high-risk groups., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Lymphoid enhancer binding factor 1 (LEF1) is consistently upregulated in chronic lymphocytic leukemia (CLL) and in a subset of large B cell lymphoma. Knowledge of LEF1 expression in Hodgkin lymphoma is limited. In this study, we used immunohistochemistry to survey LEF1 expression in various subsets of Hodgkin lymphoma, de novo classic Hodgkin lymphoma (CHL) (n = 43), Hodgkin lymphoma associated with Richter syndrome (HL-RS) (n = 20), and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) (n = 9). LEF1 expression was significantly higher in HL-RS compared with de novo CHL (12/20, 60% vs. 12/43, 28%; p = 0.0248). Only a single case (1/9; 11%) of NLPHL showed LEF1 expression. Epstein-Barr virus encoded RNA (EBER) was detected in 17 (40%) cases of de novo CHL and 14 (70%) HL-RS. Notably, we identified a correlation between LEF1 expression and EBER positivity (p = 0.0488). We concluded that LEF1 is commonly positive in CHL but not in NLPHL, and such a distinction may be helpful in this differential diagnosis. The higher frequency of LEF1 upregulation in HL-RS relative to de novo CHL suggests that these neoplasms might have different underlying pathogenic mechanisms and warrants further investigation., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Primary mediastinal (thymic) large B-cell lymphoma (PMBL) is described as almost always negative for Epstein-Barr virus (EBV). In the context of a mediastinal lymphoma, the distinction between PMBL, classical Hodgkin lymphoma, diffuse large B-cell lymphoma, and mediastinal gray-zone lymphoma can be very difficult; hence, EBV positivity often argues against PMBL. We present a 19-year-old man with mediastinal mass morphologically consistent with PMBL. The tumor expressed classic immunophenotype, including positivity for CD20, CD19, MAL, OCT2, BOB1, BCL6, CD79a, and subset positivity for CD30. However, the tumor was EBV-positive by in situ hybridization. Next-generation sequencing detected somatic mutations in XPO1 (E571K), SMARCB1 (L356fs), and MYCC (T73A). Although the immunophenotype and XPO1 mutation are characteristic of PMBL, EBV expression is uncommon. Since EBV positivity can occur in rare PMBLs, it should not be the deciding factor in the diagnosis. This is the first EBV-positive PMBL in which mutational profiling has been reported. Aside from providing diagnostic support, the finding of the XPO1 E571K mutation may suggest a targeted therapeutic option.

The formation, development and dissolution of germinal centers is a major part of immune system function. It is important to differentiate neoplastic processes from follicular hyperplasia and regressive follicular changes. Better understanding of germinal center development and dissolution also provides diagnostic clues to the underlying pathologic process. It is also important in identifying the immune basis of different pathologic entities as well as in immunotherapy decision making and follow up. In this study, we characterize the immunoarchitecture of lymphoid follicles with a focus on germinal center in one representative case, each of commonly encountered benign and malignant lymph node disorders, with morphologic and immunohistochemical alterations of germinal centers. The cases include reactive follicular hyperplasia (FH), florid follicular hyperplasia (FFH), follicular lymphoma (FL), angioimmunoblastic T-cell lymphoma (AITL), hyaline-vascular Castleman disease (HVCD), progressive transformation of germinal centers, nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), lymphocyte-rich classic Hodgkin lymphoma (LR-CHL), human immunodeficiency virus (HIV)-associated follicular dissolution and chronic lymphocytic leukemia (CLL) with proliferation centers (PC). A panel of antibodies were used namely CD3, CD20, CD10, BCL2, BCL6, CD21, CD23, CD35, FOXP1, GCET1, HGAL/GCET2, LMO2, MUM1, IgD, Ki67, PD1 and PD-L1. We found that these entities show distinct immunoarchitectural patterns of germinal center formation, development and regression, particularly, the distribution of mantle zone B-cells, follicular helper T cells (Tfh) and FDC meshworks, confirming the influence of antigenic stimulation and status of immune system in these changes. This also confirms the interrelationship of underlying immunologic mechanisms in these disease processes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

C-terminal Src kinase (CSK) functions as a negative regulator of T cell activation through inhibitory phosphorylation of LCK, so inhibitors of CSK are of interest as potential immuno-oncology agents. Screening of an internal kinase inhibitor collection identified pyridazinone lead 1 , and a series of modifications led to optimized compound 13 . Compound 13 showed potent activity in biochemical and cellular assays in vitro and demonstrated the ability to increase T cell proliferation induced by T cell receptor signaling. Compound 13 gave extended exposure in mice upon oral dosing and produced a functional response (decrease in LCK phosphorylation) in mouse spleens at 6 h post dose., Competing Interests: The authors declare the following competing financial interest(s): The authors of this manuscript are employees of Bristol-Myers Squibb., (Copyright © 2019 American Chemical Society.)

Context.—: Even though immunohistochemistry is routinely used by pathologists, evaluation of immunohistochemistry in splenic lesions remains difficult for many. Classification of benign and splenic lesions often requires a combination of hematoxylin-eosin evaluation, immunophenotyping, and sometimes molecular testing. Immunohistochemical staining is essential in evaluating many splenic lesions, and requires an understanding of the normal compartments of the spleen., Objective.—: To address different immunohistochemical features used for identification and subclassification of different lesions of the spleen, as well as in the normal compartments of the spleen., Data Sources.—: The information outlined in this review article is based on our experiences with a variety of spleen cases, on the current World Health Organization classification of hematopoietic and lymphoid tumors, and on a review of English-language articles published during 2018., Conclusions.—: Features for phenotyping normal spleen as well as a variety of splenic lesions, including littoral cell angioma and splenic marginal zone lymphoma, are discussed. Suggested immunopanels are provided to assist in the diagnosis of different lesions of the spleen.

Background: The most common nasopharyngeal lymphoma in the United States are B-cell non-Hodgkin lymphomas (B-NHL). Relatively little is known about the clinicopathologic features of these cases. In this study, we characterize a bi-institutional cohort of aggressive B-NHL primary to the nasopharyngeal area. We compare and contrast EBV-positive versus EBV-negative cases and evaluate expression of SSTR2, CD30, and PD-L1, potential markers for targeted therapeutics., Methods and Results: We retrieved 53 cases of aggressive B-NHL from the two institutions. Staining was performed for in situ EBV (EBER), CD30, SSTR2 and PD-L1. The response to initial therapy, disease-free interval, and survival at two- and five-year following initial diagnosis were used as primary clinical outcome. Overall, 13 out of 53 cases (23%) were EBV positive. CD30 expression was more frequent in EBV-positive than in EBV-negative cases (4/6 vs 1/17). Seven of 14 (50%) cases tested demonstrated expression of PD-L1 within tumor cells; the two EBV-positive DLBCL tested showed substantial PD-L1 reactivity. Six of 15 (40%) cases tested were positive for SSTR2. The three EBV-positive patients with available outcome data died within one year of diagnosis; in contrast, the EBV-negative cases showed survival rate of 100% (8/8) and 83% (5/6) at two- and five-year follow-up, respectively., Discussion: The aggressive B-NHLs of the nasopharynx show differences between EBV-positive versus EBV-negative cases. The association of EBV-positive cases with expression of CD30 and PD-L1 may be particularly informative for targeted therapies. A significant number of cases expresses SSTR2, which could render them susceptible to somatostatin analogue and peptide receptor radionuclide therapies. Finally, our limited case series suggest that EBV negativity may be associated with a better prognosis., (Copyright © 2019. Published by Elsevier Inc.)

Targeting of the PD1/PD-L1 immune checkpoint pathway has rapidly gained acceptance as a therapeutic strategy for a growing number of malignancies. Testing for expression of PD-L1 in tumor cells and immune cells has been used as a companion or complementary test for drugs targeting the PD1/PD-L1 pathway. We evaluated the results of PD-L1 testing in a large reference lab cohort. Using Food and Drug Administration-approved methods and interpretive instructions for each individual test, 62,896 cases were evaluated for PD-L1 using antibody clone 22C3, 28-8, SP142, or SP263. Case data analyzed included test results and information on tumor location and clinical history. No clinical outcome information was available and no attempt was made to correlate PD-L1 results with any other tests performed. The following numbers of cases were evaluated: 22C3 with tumor proportion score [n = 52585], 22C3 with combined positive score [n = 2631], 28-8 [n = 4191], SP142 [n = 850], and SP263 [n = 70]. In 22C3/tumor proportion score cases, the general results were as follows: negative 33.1% (n = 17,405), (low) expression 33.9% (n = 17,822), and high expression 29.5% (n = 15,486). In cases identified as metastatic, the results were as follows: negative 35.9% (n = 1411), (low) expression 30.8% (n = 1211), and high expression 30.7% (n = 1208). We found broad ranges of expression in tumor types with increasing positivity, as adenocarcinomas were reported as poorly differentiated, whereas squamous cell carcinomas showed more positivity as tumors were described as well-differentiated. The results of many individual tumor types were evaluated and showed, in general, high levels of positive expression. Practical challenges and observations of PD-L1 stain results and interpretation are also discussed.

The diagnosis of classic Hodgkin lymphoma requires immunohistochemical confirmation in most cases and one can argue for these studies as standard-of-care in the diagnostic workup. The authors propose a panel of studies for primary identification of CHL to include: CD3, CD20, CD15, CD30 and PAX5. When pattern discordances are identified, additional assessment is recommended. In the case of overexpression of B lineage markers by Hodgkin/Reed-Sternberg cells, or a differential diagnosis that includes large B-cell lymphoma or variants, additional markers recommended are: CD45, OCT2, BOB1, CD79a and MUM1/IRF4. If primary mediastinal large B cell lymphoma is considered in the differential diagnosis, suggested additional markers include: P63, CD23, CD45 and CD79a. When considering a differential diagnosis that includes anaplastic large cell lymphoma we suggest: ALK, CD45, pan T cell antigens (such as CD2, CD5, CD7, and CD43), and cytotoxic markers (granzyme, perforin, and TIA1). If peripheral T cell lymphoma or T cell lymphomas of follicular helper origin are considered in the differential diagnosis, the following panel is recommended: pan T cell antigens, CD4, CD8, one or more follicular dendritic cell markers, and assessment for Epstein-Barr virus (EBV) infection, preferably EBV encoded RNA (EBER) as assessed by in situ hybridization When the differential diagnosis includes nodular lymphocyte predominant Hodgkin lymphoma, recommended additional studies include OCT2, CD21 and/or CD23, PD1, and assessment for EBV infection. The authors recognize that these panels may not be adequate to completely characterize other lymphomas, but these panels will usually be sufficient to distinguish classic Hodgkin lymphoma from other lymphoma types., (Copyright © 2019. Published by Elsevier Inc.)

The recent 2017 update of the World Health Organization classification of lymphomas has significant changes from the previous edition. Subtypes of large B cell lymphoma and related aggressive B cell lymphomas are addressed. Clinicopathological features of entities as related to morphology, immunophenotype, cell of origin, and molecular/genetic findings are reviewed with emphasis on changes or updates in findings. Specific subtypes addressed include: T cell/histiocyte-rich large B cell lymphoma, primary diffuse large B cell lymphoma (DLBCL) of the CNS, primary cutaneous DLBCL leg-type, EBV-positive DLBCL, NOS, DLBCL associated with chronic inflammation, primary mediastinal large B cell lymphoma, intravascular large B cell lymphoma, ALK-positive large B cell lymphoma, plasmablastic lymphoma, primary effusion lymphoma, HHV8-positive diffuse large B-cell lymphoma, NOS, Burkitt lymphoma, Burkitt-like lymphoma with 11q aberration, high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, high grade B cell lymphoma, NOS, B cell lymphoma, unclassifiable, with features intermediate between DLBCL and classic Hodgkin lymphoma and large B cell lymphoma with IRF4 translocation. In addition, EBV positive mucocutaneous ulcer is addressed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The recent 2017 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues contains a number of updates under the category of lymphoid neoplasms. These changes include introduction of new entities, amended classification or terminology, and addition of newly discovered diagnostic and molecular features. In this review, we perform a focused, concise summary of selected lymphoid neoplasms and discuss changes in their classification. Rather than a comprehensive overview, we place specific emphasis on important and diagnostically relevant aspects of each entity that are novel or different from the previous WHO iteration and bring the practicing pathologist quickly up to speed with the updated classification., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This article will provide a discussion of some common autoimmune disorders that could affect the lymph nodes and potentially mimic B and T-cell lymphomas. Some of these disorders are more characteristic of individuals in the pediatric age group (autoimmune lymphoproliferative syndrome, Kawasaki disease), while others present in older individuals (rheumatoid arthritis, lupus erythematosus, sarcoidosis). A common finding that groups all of these disorders together is the overall relative preservation of the architecture, a feature that can be particularly helpful to distinguish them from many B and T-cell lymphomas. Another area of interest, that will be discussed in this review, is the pathologic manifestations that can be present in lymph nodes secondary to medications. Such alterations range from 'reactive' forms of follicular, interfollicular or paracortical hyperplasia, to specific B and T-cell lymphoproliferative disorders (particularly documented in association with methotrexate and TNF-inhibitors)., (Copyright © 2017 Elsevier Inc. All rights reserved.)

IgG4-related sclerosing disease, which now encompasses diverse organ-related disorders with various prior eponymic designations, may also present with solitary or multifocal lymph node enlargement. This review considers the histopathologic features of IgG4 lymphadenopathy (IgG4LAD), which has been subdivided by Cheuk & Chan into 5 microscopic subtypes. Those include variants that are typified by multicentric Castleman disease (MCD)-like changes, follicular hyperplasia, interfollicular lymphoplasmacytic proliferation, progressive transformation of germinal centers, and formation of inflammatory pseudotumor (IPT)-like lesions. All of them demonstrate an excess of IgG4-immunoreactive plasma cells in the inflammatory cell population. Differential diagnostic considerations for IgG4LAD include true MCD, true IPT, luetic lymphadenitis, Rosai-Dorfman disease, and inflammatory myofibroblastic tumor, among others. An interpretative distinction between malignant lymphoma and IgG4LAD is also crucial., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Juvenile xanthogranuloma is a rare histiocytic proliferation primarily affecting infants and young children, characterized by aberrant infiltration of histiocyte-derived cells in the skin, soft tissues and more rarely, visceral organs. Juvenile xanthogranuloma is generally considered to be a benign disorder; most lesions are solitary cutaneous nodules that resolve spontaneously without treatment. However, cases with extracutaneous involvement, multiple lesions, and/or systemic disease often require aggressive therapy. Though molecular studies have provided evidence of clonality in juvenile xanthogranuloma, in support of a neoplastic process, little is known about the genetic profile of juvenile xanthogranuloma. We used molecular inversion probe array technology to evaluate the genomic characteristics (copy number alterations or copy neutral-loss of heterozygosity) of 21 archived cases of juvenile xanthogranuloma (19 solitary, 1 diffuse cutaneous, 1 systemic). Four cases (19%) showed acquired, clonal alterations. Two lesions from a case of diffuse cutaneous juvenile xanthogranuloma showed distinct profiles: JXG-1a contained trisomy 5 and 17 and JXG-1b contained loss of heterozygosity in 5q. The systemic juvenile xanthogranuloma (JXG-2) showed multiple genomic alterations. Only two of 19 solitary juvenile xanthogranulomas showed abnormal genomic profiles: JXG-3 showed gains on 1q and 11q and JXG-4 showed a 7.2 Mb loss in 3p. No recurrent abnormalities were observed among these cases. The presence of non-recurrent copy number alterations in a subset of samples implies that copy number changes are unlikely driving pathogenesis in juvenile xanthogranuloma, but may be acquired during disease progression. The presence of genomic abnormalities in more advanced cases (ie, systemic and diffuse cutaneous juvenile xanthogranuloma) supports this notion, particularly as the advanced cases of juvenile xanthogranuloma presented more genomic complexity.

Follicular dendritic cell sarcoma is a rare malignant neoplasm of dendritic cell origin that is currently poorly characterized by genetic studies. To investigate whether recurrent genomic alterations may underlie the biology of follicular dendritic cell sarcoma and to identify potential contributory regions and genes, molecular inversion probe array analysis was performed on 14 independent formalin-fixed, paraffin-embedded samples. Abnormal genomic profiles were observed in 11 out of 14 (79%) cases. The majority showed extensive genomic complexity that was predominantly represented by hemizygous losses affecting multiple chromosomes. Alterations of chromosomal regions 1p (55%), 2p (55%), 3p (82%), 3q (45%), 6q (55%), 7q (73%), 8p (45%), 9p (64%), 11q (64%), 13q (91%), 14q (82%), 15q (64%), 17p (55%), 18q (64%), and 22q (55%) were recurrent across the 11 samples showing abnormal genomic profiles. Many recurrent genomic alterations in follicular dendritic cell sarcoma overlap deletions that are frequently observed across human cancers, suggesting selection, or an active role for these alterations in follicular dendritic cell sarcoma pathogenesis. In support of a tumor suppressor-driven biology, homozygous deletions involving tumor suppressor genes CDKN2A, RB1, BIRC3, and CYLD were also observed. Neither recurrent gains nor amplifications were observed. This genomic characterization provides new information regarding follicular dendritic cell sarcoma biology that may improve understanding about the underlying pathophysiology, provide better prognostication, and identify potential therapeutic markers for this rare disease.

Objectives: T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a morphologic variant of large B-cell lymphoma whose flow cytometry findings are not well characterized., Methods: Nineteen cases with flow cytometric immunophenotyping were identified from the case records of four institutions between 2001 and 2016., Results: In most cases, neoplastic B cells were not detected by flow cytometry. Overall, cases showed a predominance of CD4+ T cells, which in some cases was marked. Significant coexpression of CD57 was seen on CD4+ T cells where this marker was analyzed, which correlated with PD-1 expression. Two cases also showed a profound systemic B-cell lymphopenia, which was associated in one case with hypogammaglobulinemia., Conclusions: Overall, our work challenges previous findings that cases of THRLBCL are rich in CD8+ T cells and highlights parallels between THRLBCL and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Also, an association of THRLBCL with systemic B-cell lymphopenia has not been previously reported but may represent an underrecognized manifestation., (© American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Small lymphocytic lymphoma/chronic lymphocytic leukemia (CLL/SLL) and mantle cell lymphoma (MCL) usually are distinctly different in regard to clinical presentation, morphology, immunophenotype and molecular/genetic findings. In spite of this, select cases may show overlapping characteristics and represent a diagnostic challenge. Recently LEF1 staining was identified as a fairly characteristic finding in CLL/SLL, with positivity identified in up to 95% of cases. LEF1 staining has not been reported as being present in cases of MCL, making this stain a useful tool in distinguishing these diagnoses. We identified an index case of MCL with cyclin D1 expression and the presence of the typical t(11;14) IGH-CCND1, which expressed LEF1. Subsequently, we assessed LEF1 immunohistochemical staining in a series of 23 cases of MCL, as confirmed by staining for cyclin D1 and/or SOX11. We found expression present in one additional case, and evaluated some published literature suggesting a frequency of 4-9% expression of LEF1 by MCL. LEF1 expression by immunohistochemistry in MCL is unusual but can be seen rarely, and could represent a potential diagnostic pitfall., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We report a case of Epstein-Barr virus (EBV)-associated T-cell lymphoma of gastrointestinal (GI) tract from a 70-year-old white woman who initially presented with a widespread GI inflammation and gastric obstruction. Initial biopsies of the GI tract showed severe chronic inflammation in the esophagus, stomach, and the small intestine. Celiac disease and inflammatory bowel disease were ruled out. The patient was treated with partial gastrectomy. Histology showed gastric wall thickening with EBV-positive, mixed lymphocytic and plasma cell infiltration in the mucosa, and thickening and fibrosis of the submucosa. She developed EBV-associated T-cell lymphoma of the GI tract one and a half years later and expired due to multiorgan failure. The T-cell lymphoma diffusely infiltrated the GI wall without forming a mass lesion. The lymphoma expressed EBV and cytotoxic molecules but lacked common features of extranodal natural killer/T-cell lymphoma nasal type, such as angioinvasion/angiodestruction, necrosis, or CD56 expression. Immunoglobulin heavy chain (IGH) gene and T-cell receptor-γ gene rearrangements and EBV-positive cells were detected at the early stage of the disease. While IGH clones were transient, T-cell clones and EBV-positive cells progressively increased over the disease course. We conclude that this case is best classified as EBV-associated peripheral T-cell lymphoma of GI tract. Age-related immune senescence may have contributed to the uncontrolled GI inflammation and subsequent transformation to T-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma worldwide. The current World Health Organization classification includes several subtypes based on a combination of clinical, immunohistochemical, and genetic differences. Other aggressive variants of B-cell lymphomas, including Burkitt lymphoma and double-hit lymphomas are part of the differential diagnosis and often have overlapping features with DLBCL. In this study, we evaluated 760 of cases of DLBCL and other aggressive B-cell lymphomas using a relatively uniform immunohistochemical panel and genetic methods. We assessed the frequency of different subtypes and locations and documented distinctive immunophenotypic and genetic findings of these cases. Most cases in the study group were DLBCL (89%), including 38 CD5+ DLBCL, 28 T-cell/histiocyte-rich large B-cell lymphomas, and 33 Epstein-Barr virus-positive DLBCL (including 6 cases in elderly patients). The study also included 39 Burkitt lymphoma and 39 cases of double-hit lymphoma. In general, our results support the World Health Organization classification approach as well as other studies of DLBCL. In this study, we focus on specific issues of interest including cell-of-origin classification testing, comparing the Hans classifier with the tally classifier, correlation of MYC immunohistochemistry with MYC fluorescence in situ hybridization, and Epstein-Barr virus positivity in aggressive B-cell lymphomas., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The diagnosis of "B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma" represents an indeterminate or equivocal decision in relation to management because there remain differences in the management of Hodgkin and non-Hodgkin lymphomas. We developed a scoring system for this group of lymphomas using markers that are traditionally associated with diagnosis of classical Hodgkin lymphoma (CHL) and immunophenotypic markers associated with the "B-cell program" expressed in normal B cells., Materials and Methods: This system emphasized known criteria used to diagnose CHL that are rare in B-cell lymphoma (BCL) [CD15+, CD45-, CD20- or weak/variable, PAX5+ (weak or moderate), CD79a-, OCT-2-/BOB.1- or OCT-2+/BOB.1- or OCT-2-/BOB.1+, EBV+] versus findings that are common in BCL in contrast to CHL (CD15-, CD45+, CD20+ strong, PAX5+ strong, CD79a+, OCT-2+/BOB.1+, EBV-). After a preliminary test trial, MUM1 staining was also added. Results associated with CHL were assigned a score of +1 and score associated with BCL were assigned a score of -1. In the final grading system, a maximum score of +6 is possible for CHL and -6 for BCL., Results: An initial series of 38 cases was evaluated using a proprietary system that allows analysis of multiple stains on individual cells in a single section. An additional 23 cases were evaluated with results blinded until after scoring was performed. In general there was high concordance among cases originally diagnosed as CHL with high scores (score +4 to +6). Cases originally diagnosed as gray zone lymphomas exhibited a broader range of scores (+3 to -4). Cases of BCLs had low scores (-3 to -6)., Conclusions: The primary goal of this study was to create a scoring system that allows a cumulative quantitative measure of immunohistochemical markers, based on expected results to compare cases that might have overlapping features. In most cases, scores that trend to one extreme or another are likely representative of CHL or BCL and do not lie in the gray zone. This scoring system allows for practical resolution of many borderline cases and provide some guidance in difficult cases.

Aims: Crystal-storing histiocytosis (CSH) is a rare lesion composed of histiocytes with abnormal intralysosomal accumulation of immunoglobulin (Ig) as crystals, reported in patients with plasmacytic/lymphoplasmacytic neoplasms. The aims of this study were to report the clinicopathological features of 13 patients with CSH, and to describe the proteomic composition of the crystals in three cases analysed by mass spectrometry (MS)., Methods and Results: There were seven men and six women, with a median age of 60 years (range, 33-79 years). CSH was generalized in one patient (8%) and localized in 12 (92%) patients, involving various sites. CSH was associated with a low-grade B-cell lymphoma with plasmacytoid differentiation or a plasma cell neoplasm in all cases. In 10 (77%) cases, CSH represented >50% of the neoplastic infiltrate. According to immunohistochemical studies, histiocytes were positive for monotypic kappa in 5 (50%) cases, and for monotypic lambda in 4 (40%) cases; in 1 (10%) case, the results were equivocal. MS analysis of the histiocyte contents in all three tested cases showed a predominance of variable-region fragments of Ig light and/or heavy chains., Conclusions: CSH is frequently associated with an underlying lymphoplasmacytic neoplasm. MS findings suggest that Ig alterations and/or possibly defects in the ability of histiocytes to process Ig play a role in pathogenesis., (© 2015 John Wiley & Sons Ltd.)

This review examines handling and processing of spleen biopsies and splenectomy specimens with the aim of providing the pathologist with guidance in optimizing examination and diagnosis of splenic disorders. It also offers recommendations as to relevant reporting factors in gross examination, which may guide diagnostic workup. The role of splenic needle biopsies is discussed. The International Spleen Consortium is a group dedicated to promoting education and research on the anatomy, physiology, and pathology of the spleen. In keeping with these goals, we have undertaken to provide guidelines for gross examination, sectioning, and sampling of spleen tissue to optimize diagnosis (Burke). The pathology of the spleen may be complicated in routine practice due to a number of factors. Among these are lack of familiarity with lesions, complex histopathology, mimicry within several types of lesions, and overall rarity. To optimize diagnosis, appropriate handling and processing of splenic tissue are crucial. The importance of complete and accurate clinical history cannot be overstated. In many cases, significant clinical history such as previous lymphoproliferative disorders, hematologic disorders, trauma, etc, can provide important information to guide the evaluation of spleen specimens. Clinical information helps plan for appropriate processing of the spleen specimen. The pathologist should encourage surgical colleagues, who typically provide the specimens, to include as much clinical information as possible., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Survivin, a member of the inhibitor of apoptosis protein family, is overexpressed in a variety of human neoplasms. The prognostic significance of survivin expression in diffuse large B-cell lymphoma patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is unclear. We used standard immunohistochemistry methods to quantify survivin expression in 463 patients with de novo diffuse large B-cell lymphoma who received the R-CHOP. Of the 463 patients, 269 (58%) had survivin overexpression with a cutoff of >25%, associated with an International Prognostic Index score of >2 (P=0.015), disease in ≥2 extranodal sites (P=0.011), and a high Ki-67 index (P<0.0001). Among patients with activated B cell-like disease, the overall survival rate of survivin-positive patients was significantly lower than that of survivin-negative patients (P=0.033); multivariate analysis confirmed that in these patients, survivin overexpression was an independent prognostic factor for survival. Among patients with wild-type p53 overexpression, the overall survival and progression-free survival rates of the survivin-positive group were significantly lower than those of the survivin-negative group (P=0.035 and P=0.04 respectively). In STAT3-positive patients, survivin overexpression was associated with significantly better survival. Among patients with activated B cell-like disease, survivin-positive compared with survivin-negative groups had significantly different gene expression signatures, including genes involved in mitosis or tumor cell proliferation. Our results indicate that survivin is an independent prognostic factor for poor outcome in patients with activated B cell-like disease treated with the R-CHOP regimen, and patients with survivin-positive activated B cell-like diffuse large B-cell lymphoma seem to benefit less from this treatment and may require additional novel agents.

Context: Diffuse large B-cell lymphoma is the most commonly diagnosed subtype of lymphoma worldwide. The current World Health Organization (WHO) classification includes several subtypes, based on a combination of clinical, immunohistochemical, and genetic differences. Immunohistochemical staining is essential in evaluating diffuse large B-cell lymphoma and many related large B-cell lymphomas and aggressive B-cell lymphomas., Objective: To address different immunohistochemical features used for identification, subclassification, prognosis and in some cases, therapy, of diffuse large B-cell lymphoma and related lymphomas., Data Sources: The information outlined in this review article is based on our experiences with routine cases, on the current WHO classification of hematopoietic and lymphoid tumors, and on a review of English-language articles published throughout 2014., Conclusions: Features and diagnostic criteria of diffuse large B-cell lymphoma, aggressive variants of B-cell lymphomas, including Burkitt lymphoma and "double-hit" lymphomas, are discussed. Identification of cell of origin (germinal center type versus activated B-cell type) is discussed at length. Finally, practical approaches for diagnosis are discussed.

BRAF V600E mutations have been reported in several histiocytic and dendritic cell neoplasms. In this case series, we report BRAF V600E-positive histiocytic and dendritic cell neoplasms in association with lymphomas and lymphoid proliferations. This is a review of cases with immunohistochemistry for BRAF V600E, with additional immunohistochemistry to categorize tumors. We report the first case of BRAF V600E-positive indeterminate cell tumor in association with angioimmunoblastic T-cell lymphoma. We also report a case of BRAF V600E-positive interdigitating dendritic cell sarcoma in a patient with positive B-cell polymerase chain reaction. It is unclear if these neoplasms developed as transdifferentiation of lymphoid neoplasms or if they developed independently. These cases illustrate the expanding spectrum of BRAF V600E-positive histiocytic and dendritic cell tumors and suggest that attention should be paid to lymphomas for possible coincident presentation of these disorders., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Littoral cell angioma (LCA) is a rare vascular tumor of the spleen. It has an immunohistochemical staining pattern that is somewhat distinctive but can still be occasionally confused with other vascular and stromal proliferations in the spleen. In this study, LCA was evaluated using Ets-related gene (ERG) and Wilms tumor-1 (WT-1), relatively recently described vascular markers. In addition, other vascular lesions including normal spleen, hemangiomas, hamartoma, peliosis, and sclerosing angiomatoid nodular transformation were evaluated using these stains. In LCA, ERG stains the endothelial cells of the tumor as expected. ERG also was uniformly positive in vascular elements of other lesions except peliosis. However, in contrast to most other vascular elements, LCA was negative for WT-1 staining. This staining pattern may prove useful in diagnosing LCA and may provide insight into the derivation of the distinctive tumor., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The marine natural products amphidinolide C (1) and F (4) differ in their side chains but share a common macrolide core with a signature 1,4-diketone substructure. This particular motif inspired a synthesis plan predicating a late-stage formation of this non-consonant ("umpoled") pattern by a platinum-catalyzed transannular hydroalkoxylation of a cycloalkyne precursor. This key intermediate was assembled from three building blocks (29, 41 and 47 (or 65)) by Yamaguchi esterification, Stille cross-coupling and a macrocyclization by ring-closing alkyne metathesis (RCAM). This approach illustrates the exquisite alkynophilicity of the catalysts chosen for the RCAM and alkyne hydroalkoxylation steps, which activate triple bonds with remarkable ease but left up to five other π-systems in the respective substrates intact. Interestingly, the inverse chemoselectivity pattern was exploited for the preparation of the tetrahydrofuran building blocks 47 and 65 carrying the different side chains of the two target macrolides. These fragments derive from a common aldehyde precursor 46 formed by an exquisitely alkene-selective cobalt-catalyzed oxidative cyclization of the diunsaturated alcohol 44, which left an adjacent acetylene group untouched. The northern sector 29 was prepared by a two-directional Marshall propargylation strategy, whereas the highly adorned acid subunit 41 derives from D-glutamic acid by an intramolecular oxa-Michael addition and a proline-mediated hydroxyacetone aldol reaction as the key steps; the necessary Me3 Sn-group on the terminus of 41 for use in the Stille coupling was installed via enol triflate 39, which was obtained by selective deprotonation/triflation of the ketone site of the precursor 38 without competing enolization of the ester also present in this particular substrate., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Classical Hodgkin lymphoma can be diagnosed with confidence in the majority of cases, but there is a significant subset that remains a diagnostic challenge. The authors have investigated the utility of a novel hyperplexing technology, MultiOmyx™, which may be applied to stain with >60 antibodies on single tissue sections from formalin-fixed paraffin-embedded tissue as an aid to the diagnosis of classical Hodgkin lymphoma. The multiplexing protocol included CD30, CD15, PAX-5, CD20, CD79a, CD45, BOB.1, OCT-2, and CD3 antibodies. The technology showed a high degree of sensitivity, specificity, and precision. Comparison studies with routine hematoxylin and eosin and immunohistochemical assessment of hematopathology cases in which classical Hodgkin lymphoma was included in the differential diagnosis showed concordance in 54 of 56 cases, with the 2 discordant cases illustrating the potential of this multiplexed immunofluorescence technology to improve on traditional immunohistochemistry for classical Hodgkin lymphoma diagnosis. This technology is practical for routine diagnosis and may be particularly useful in cases in which the sample size is limited, few Hodgkin-like cells are present, or in CD30-positive lymphoma cases with difficult morphology. MultiOmyx may potentially benefit other areas of research and diagnostic pathology.

Hodgkin lymphoma (HL) is classified into 2 largely distinct subgroups, namely nodular lymphocyte predominant HL (NLPHL) and classic HL (CHL). CHL is further divided into nodular sclerosis, lymphocyte-rich, mixed cellularity (MCCHL) and lymphocyte-depleted (LDCHL) subtypes. In industrialized nations, Epstein-Barr virus (EBV) has been associated with all types of CHL, especially the MCCHL and LDCHL subtypes, but is rare in NLPHL. We report 8 cases of EBV-positive NLPHL occurring in patients in the United States. All 8 patients have no history of immunosuppression and presented with localized or systemic lymphadenopathy. Histologically, 6 cases had a vaguely nodular pattern and 2 cases had a nodular and diffuse pattern. In all cases, lymphocyte predominant (LP) cells were observed in a background of small lymphocytes and histiocytes. Immunohistochemical analysis showed that the LP cells in all cases were positive for CD20, CD79a, PAX5, OCT2, and CD45 and were negative for CD15. CD30 was expressed variably in 7 cases. EBV encoded RNA was present in all LP cells in 5 cases and in a subset of LP cells in 3 cases. One patient was treated with radiation therapy and 7 patients received chemotherapy, including 4 of 7 patients who underwent autologous stem cell transplantation. EBV infection is a rare primary or secondary event in NLPHL that correlates with poorer prognosis and often requires more aggressive therapy. The variable expression of CD30 in most of these cases could be the result of EBV infection., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Primary osteoma cutis (cutaneous ossification) is an uncommon disease in which there is bone formation within the skin in the absence of a demonstrable pre-existing condition. Osteoma cutis is a chronic and benign condition. We report a case of a 45-year-old man who developed extramedullary acute leukemia with a myeloid immunophenotype (myeloid sarcoma) with its initial presentation within an isolated pre-existing osteoma cutis in the post-auricular scalp without evidence of systemic acute leukemia or chronic myeloid stem cell disorders. The tumor was surgically excised without complications. Four months later, acute leukemia recurred in the contralateral posterior mandible and showed an immunophenotype consistent with acute lymphoblastic leukemia/lymphoma. The patient now has been treated by standard protocols for acute leukemia. The diagnosis of an extramedullary acute leukemia is challenging because of its inconsistent clinical and histopathologic presentations. Extramedullary acute leukemia developing in a pre-existing osteoma cutis is very unusual and has not been previously reported in the literature., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Gastrointestinal lymphomas can be difficult to diagnose, particularly in small samples, when early in development, or when of unusual types. In this review, we describe lymphoid proliferations in the gastrointestinal tract in a location-based manner, including, mouth, esophagus, stomach, small intestine, and large bowel. For the purpose of differential diagnosis, benign mimics of lymphoma are also described. Lymphoma types that are specifically addressed include plasmablastic, extranodal natural killer/T-cell-nasal type, extranodal marginal zone lymphoma (eg, mucosa-associated lymphoid tissue lymphoma), diffuse large B cell, primary follicular of small intestine, enteropathy-associated T cell, and Burkitt and mantle cell. Immunohistochemical markers useful in the diagnostic approach are elaborated in detail., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: To examine interactions among clinical factors and pathologic biomarkers in predicting the outcome of patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab-based immunochemotherapy., Methods: In 85 patients treated at a single institution, clinicopathologic variables were analyzed, including the International Prognostic Index (IPI); germinal/nongerminal center phenotype; MYC, p53, BCL2, Ki-67, and Epstein-Barr virus (EBV) expression; and MYC translocation status., Results: In univariate analysis, overall survival (OS) was worse for patients with high IPI scores, nongerminal center phenotype, high MYC and p53 expression by immunohistochemistry, and EBV positivity. In multivariable analysis, p53 expression was the strongest prognostic factor (P < .05) independent of IPI and cell of origin. A significant positive association between p53 and MYC expression was found. Moreover, coexpression of p53/MYC had an enhanced negative effect on OS independent of BCL2 expression., Conclusions: Immunohistochemical assessment of p53, particularly in combination with MYC, could be useful in identifying a high-risk subgroup of DLBCL.

Histiocytic disorders have been noted to have evidence of transdifferentiation; examples of cases with combinations of different lineages have been shown. In our index case, we identified interdigitating dendritic cell (IDC) differentiation in a case of Langerhans cell histiocytosis (LCH). Little is currently known about the genetics of IDC sarcoma (IDCS) because they are exceedingly rare. Using array comparative genomic hybridization (aCGH), we evaluated 4 cases of IDCS and compared them with our index case, as well as genetic abnormalities previously found in LCH. Four cases of paraffin-embedded samples of IDCS and 1 case of LCH with IDC differentiation were evaluated using aCGH. Array CGH results showed no abnormalities in a case of LCH with interdigitating cell differentiation. In 3 of 4 cases of IDCS, genetic abnormalities were identified; 1 case had no identifiable abnormalities. Interdigitating dendritic cell sarcoma case 1 had gains of 3q and 13q; IDCS case 2 had trisomy 12; IDCS case 3 had deletions of 7p, 12p, 16p, 18q, 19q, and 22q; and IDCS case 4 had no detectable abnormalities. Our index case, LCH with IDC differentiation, showed no abnormalities by aCGH. A number of LCH cases do not have detectable genetic abnormalities. In contrast, 3 of 4 cases of IDCS evaluated had identifiable abnormalities by aCGH. Furthermore, 2 of these shared abnormalities, albeit of large genetic regions, with published abnormalities seen in LCH. No recurrent abnormalities were identified in the IDCS cases. However, the possibility of a relationship between IDCS and LCH cannot be entirely excluded by these results., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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.