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Mast cell sarcoma (MCS) is an exceedingly rare form of mastocytosis characterized by invasive malignant mast cell growth and metastatic potential. Diagnosis of MCS is very challenging due to its marked morphologic variations and significant immunophenotypic overlap with other neoplasms. In this study, we undertook an extensive study of 10 cases of MCS from our series, with review of additional 24 cases from the literature, to better clarify the clinicopathologic and molecular features of MCS. From the analyses of our 10 cases, MCS equally involved males and females with a median age of 54.5 years (range 1-63). The bone was the most common site of involvement, as noted in 9/10 of cases. Two patients had prior germ cell tumors (mediastinal germ cell tumor and ovarian dysgerminoma), and concurrent systemic mastocytosis was noted in one of nine patients. Serum tryptase levels were elevated in 6/7 of patients, and 3/9 of patients had mast cell activation symptoms. Morphologically, the tumor cells were typically large and pleomorphic with frequent reactive eosinophils. By immunohistochemical staining, MCS consistently expressed CD43 (8/8), CD117 (10/10), and mast cell tryptase (10/10), as well as CD13 (3/3) and CD33 (10/10), with variable positivity of CD2 (1/9), CD25 (4/9), CD30 (5/8), and CD68 (5/9). Notably, KIT D816V was not detected in nine cases in our study, although two cases had other mutations of KIT gene. Seven out of eight patients received chemotherapy with or without radiotherapy. However, the response was poor, and four out of eight patients died within a median follow-up interval of five months. Taken together, there are no standardized therapeutic regimens available for MCS at this time, and the prognosis is dismal. Therefore, it is critical to further investigate and characterize this rare entity, with the hope of improving diagnostic accuracy and providing more effective, targeted therapies.

Context.— Plasmablastic lymphoma (PBL) is a rare aggressive lymphoma, usually positive for CD138 and frequently occurring in the oral cavity of human immunodeficiency virus (HIV) patients. Up to 10% of cases are negative for CD138 and diagnostically very challenging. Objective.— To investigate the appropriate approach to diagnose CD138− plasmablastic lymphoma and avoid misdiagnosis. Design.— We studied 21 cases of CD138− PBL from multiple large institutes in the United States and 21 cases from literature. Results.— CD138− PBLs were positive for different B/plasma cell markers at various percentages: MUM1 (94.4%; 34 of 36), OCT2 (70.6%; 12 of 17), immunoglobulin light chains (68.8%; 22 of 32), CD38 (68.4%; 13 of 19), CD79a (34.2%; 13 of 38), and PAX5 (15.6%; 5 of 32), suggesting that MUM1, OCT2, immunoglobulin light chains, and CD38 are useful markers to help establish the lineage. A total of 83% of cases (30 of 36) were extraoral lesions. Extraoral lesions showed much lower Epstein-Barr virus (EBV) infection rates (16 of 30; 53.3%) and had worse prognosis. MYC was positive in 80% (8 of 10) of EBV+ cases and 40% (2 of 5) EBV− cases, indicating the importance of MYC in pathogenesis, especially in EBV+ cases. Conclusions.— Our study emphasizes that CD138− PBLs tend to be extraoral lesions, with much lower EBV infection rates, and diagnostically very challenging. Accurate diagnosis requires a thorough investigation and workup by using appropriate markers.

Hepatic involvement by a T-cell neoplasm is rare and often challenging to diagnose in liver biopsies. We collected 40 cases of T-cell neoplasms diagnosed in the liver from five large academic institutions to assess the clinicopathologic features. The patients included 11 women and 29 men, with a median age of 54 (range: 2-75) years and a high mortality rate (31/37, 83.8%). Fourteen (35%) patients were diagnosed with hepatosplenic T-cell lymphoma (HSTCL), 13 (32.5%) peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), and 13 (32.5%) other types of T-cell neoplasms. Patients with HSTCL were much younger and had worse survival than PTCL-NOS and other T-cell neoplasms (P 0.05). On imaging studies, 20 cases (50%) showed abnormalities, including 10 with mass lesions that correlated with normal or cholestatic pattern enzyme elevation. Histomorphological analysis revealed four main patterns; with the exception of mass forming lesions (pattern 4; n = 8), cases with sinusoidal predominant (pattern 1; n = 12), portal predominant with sinusoidal infiltrates (pattern 2; n = 13) or lobular aggregates (pattern 3; n = 5) demonstrated small to medium lymphocytes resembling a reactive/inflammatory process. In addition, we described two cases of T-cell large granular lymphocytic leukemia that mimicked HSTCL, and a case of aggressive post-transplant lymphoproliferative disorder that developed after chronic Epstein-barr virus (EBV) infection, suggesting the importance of EBV testing in some lymphoma cases. As the largest cohort of T-cell neoplasms in liver, our study provides critical data on disease frequency, distribution, and clinicopathologic features that are essential for accurate diagnosis.

While the lung is frequently involved by systemic lymphoma, primary pulmonary lymphoma accounts for less than 1% of all extranodal ymphomas. In particular, T-cell lymphoma is very rare in the lung, as a primary or secondary lesion. Patients with pulmonary T-cell lymphoma usually present with cough, dyspnea, pain, fever, recurrent infections, and hemoptysis. Typical radiologic features include pulmonary nodules, consolidation, solid pulmonary opacities, cystic changes, hilar adenopathy, and pleural effusions. Patients with these clinical and radiologic findings are frequently presumed to have pneumonia and initially treated with empirical antibiotics. Therefore, CT-guided needle biopsy, bronchoscopic examination, or even wedge biopsy should be considered when clinical symptoms show deterioration despite adequate antibiotic therapy. Precise pathologic diagnosis and molecular characterization are recommended in all cases, following the World Health Organization (WHO) classification. Principles of treatment typically vary with the different histologic types of T-cell lymphoma.

Mast cell leukemia with associated hematologic neoplasm (MCL-AHN) is a rare and highly aggressive entity that remains understudied due to the paucity of cases. We present a case of a 45-year-old man who was concurrently diagnosed with mast cell leukemia and acute myeloid leukemia. We identified four additional patients who had MCL-AHN in our institution and performed whole-exome sequencing of all available tumors. Our series revealed a novel and identical NR2F6 variant shared among two of the patients. This case series and sequencing results demonstrate the importance of fully characterizing rare tumors that are resistant to treatment.

Introduction Infantile leukemia encompasses a heterogeneous group which needs stratifying for treatment selection. Methods We collected 78 cases of infantile leukemia and retrospectively analyzed their clinicopathological data. Results Infantile leukemia featured a ratio of acute myeloid leukemia (AML) to B-lymphoblastic leukemia (B-ALL) of 1:2, with a better survival for AML than B-ALL (median survival 36 vs 24 months). When stratified by age, "early" infantile B-ALL (2-6 months) showed a high rate of KMT2A rearrangement (100%), similar to the rate seen in congenital B-ALL (1 month) (100%) and higher than seen in "late" infantile B-ALL (≥7 months) (68%). The three categories of infantile B-ALL exhibited an age-dependent increase in survival (median survival 8.5, 24, and >24 months, respectively). The age-dependent survival benefit remained after excluding the cases negative for KMT2A rearrangement. Conversely, infantile AML lacked an age-dependent pattern of survival. Conclusion The clinical outcome of infantile leukemia depends on the type of leukemia. Given the age-dependent survival, infantile B-ALL can be divided into three subcategories.

Simple Summary Primary effusion lymphoma (PEL) is a rare HHV8 driven large B-cell lymphoma. It is often associated with HIV infection and seldom occurs in HIV-negative immunocompromised patients. Patients with PEL usually present with effusion only, but occasionally with an extracavitary mass, or both. This retrospective study aimed to better characterize the clinicopathological features of PEL by comparing effusion-only PEL versus the extracavitary-only PEL and HIV-positive versus HIV-negative cases in a large cohort of 70 patients. All 70 (100%) cases were positive for HHV8. Fifty-six (80%) patients had HIV infection. Patients presenting with effusion only versus extracavitary disease were associated with different clinicopathologic features. After a median follow-up time of 40 months (range 0–96), 26 of 52 (50%) patients with clinical follow-up died, and the median survival was 42.5 months. PEL is an aggressive lymphoma with a poor prognosis, regardless of extracavitary presentation or HIV status. Abstract Primary effusion lymphoma (PEL) is a rare type of large B-cell lymphoma associated with human herpesvirus 8 (HHV8) infection. Patients with PEL usually present with an effusion, but occasionally with an extracavitary mass. In this study, we reported a cohort of 70 patients with PEL: 67 men and 3 women with a median age of 46 years (range 26–91). Of these, 56 (80%) patients had human immunodeficiency virus (HIV) infection, eight were HIV-negative, and six had unknown HIV status. Nineteen (27%) patients had Kaposi sarcoma. Thirty-five (50%) patients presented with effusion only, 27 (39%) had an extracavitary mass or masses only, and eight (11%) had both effusion and extracavitary disease. The lymphoma cells showed plasmablastic, immunoblastic, or anaplastic morphology. All 70 (100%) cases were positive for HHV8. Compared with effusion-only PEL, patients with extracavitary-only PEL were younger (median age, 42 vs. 52 years, p = 0.001), more likely to be HIV-positive (88.9% vs. 68.6%, p = 0.06) and EBV-positive (76.9% vs. 51.9%, p = 0.06), and less often positive for CD45 (69.2% vs. 96.2%, p = 0.01), EMA (26.7% vs. 100%, p = 0.0005), and CD30 (60% vs. 81.5%, p = 0.09). Of 52 (50%) patients with clinical follow-up, 26 died after a median follow-up time of 40.0 months (range 0–96), and the median overall survival was 42.5 months. The median OS for patients with effusion-only and with extracavitary-only PEL were 30.0 and 37.9 months, respectively (p = 0.34), and patients with extracavitary-only PEL had a lower mortality rate at the time of last follow-up (35% vs. 61.5%, p = 0.07). The median OS for HIV-positive and HIV-negative patients were 42.5 and 6.8 months, respectively (p = 0.57), and they had a similar mortality rate of 50% at last follow-up. In conclusion, patients presenting with effusion-only versus extracavitary-only disease are associated with different clinicopathologic features. PEL is an aggressive lymphoma with a poor prognosis, regardless of extracavitary presentation or HIV status.

This case illustrates a rare and aggressive entity in AIDS‐related lymphoproliferative disorders and highlights the importance and challenges of recognizing PEL outside of cavitary lesions.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL), which accounts for 30–40% of adult NHL with 27,650 estimated new cases diagnosed in the United States in 2016. DLBCL is defined as a B-cell neoplasm with a diffuse growth pattern of large tumor cells with a nuclear size larger than that of a histiocyte nucleus or more than twice that of a normal small lymphocyte.

Excisional biopsy of lymph node is a routine procedure for evaluating lymphoid pathology in patients with lymphadenopathy. A standard workup to rule out lymphoma is a comprehensive study, including histologic evaluation, immunohistochemical analysis, flow cytometry, cytogenetic study (i.e., FISH for targeted cytogenetic abnormalities), and/or molecular diagnostic tests. This chapter covers some general principles for handling specimens of lymphoma workup, clinical correlation with types of lymphoma, common morphological patterns of lymphomas or mimics, and judicial application of ancillary tests, based on clinical presentations and initial morphologic evaluation.

Rare B-cell neoplasms with plasmablastic differentiation may aberrantly express CD3 by immunohistochemical staining, which places a great challenge for diagnosis. We here studied 17 cases of CD3+ plasmablastic B-cell neoplasms, including 12 plasmablastic lymphomas and 5 plasmablastic plasma cell myelomas. All 17 cases occurred in the extranodal sites with a male predominance (13/17). Four cases were initially misinterpreted by outside institutions, among which three were diagnosed as 'peripheral T-cell lymphoma, not otherwise specified' and one was classified as 'poorly differentiated neuroendocrine carcinoma'. The plasmablastic cells were present in all 17 cases diffusely or in a subset of tumor cells. CD3 expression was mostly diffuse (12/17) and moderate to strong (11/16) with a cytoplasmic staining pattern (14/16). Other T-cell markers were nearly absent, including CD2 (0/10), CD4 (1/13), CD5 (0/14), CD7 (0/11), and CD8 (0/13). CD138 was positive in all 17 cases and CD79a was variably positive in 8 of 14 cases. Only one case had immunoreactivity to CD20 (1/17) and PAX5 (1/12). CD56 expression and EBV infection were detected in 8/15 and 6/17, respectively. No HHV8 infection was noted in all 11 cases tested. Most cases (11/13) revealed either kappa or lambda light chain restriction. Of the nine cases studied, six had clonal IGH rearrangements but no clonal TRG rearrangements. Our study further emphasizes that the accurate classification of CD3+ plasmablastic neoplasms requires thorough morphologic examination, incorporation of more B-cell and T-cell markers in addition to CD3 and CD20, frequent addition of CD138 staining, and utilization of necessary molecular and genetic studies.

Chemotherapeutic agents, e.g., cytarabine and doxorubicin, cause DNA damage. However, it remains unknown whether such agents differentially regulate cell cycle arrest in distinct types of B-cell lymphomas, and whether this phenotype can be exploited for developing new therapies. We treated various types of B cells, including primary and B lymphoma cells, with cytarabine or doxorubicin, and determined DNA damage responses, cell cycle regulation and sensitivity to a Wee1 inhibitor. We found that cyclin A2/B1 upregulation appears to be an intrinsic programmed response to DNA damage; however, different types of B cells arrest in distinct phases of the cell cycle. The Wee1 inhibitor significantly enhanced the apoptosis of G2 phase-arrested B-cell lymphomas by inducing premature entry into mitosis and mitotic catastrophe, whereas it did not affect G1/S-phase-arrested lymphomas. Cytarabine-induced G1-arrest can be converted to G2-arrest by doxorubicin treatment in certain B-cell lymphomas, which correlates with newly acquired sensitivity to the Wee1 inhibitor. Consequently, the Wee1 inhibitor together with cytarabine or doxorubicin inhibited tumor growth in vitro and in vivo more effectively, providing a potential new therapy for treating B-cell lymphomas. We propose that the differential cell cycle arrest can be exploited to enhance the chemosensitivity of B-cell lymphomas.

Erdheim-Chester disease (ECD) is a rare nonLangerhans cell histiocytosis. Although approximately 50% of cases eventually involve the central nervous system (CNS), the CNS has seldom been reported as the initial biopsy site. The diagnosis of CNS ECD can be challenging due to morphologic overlap with reactive histiocytic proliferation, Langerhans cell histiocytosis (LCH), and extranodal Rosai-Dorfman disease (RDD). We present 3 cases from our files that illustrate the protean manifestations of ECD. Case 1 was a 47-year-old man with ataxia, dysarthria, and intermittent ophthalmoplegia whose cerebellar biopsy had shown only profuse, nonspecific Rosenthal fiber-rich piloid gliosis; ECD was diagnosed only at autopsy. The gliosis and marked variations in histiocyte morphology in different anatomical sites added to the diagnostic challenge. Case 2 was a 67-year-old female with chronic progressive symptoms and a pontine lesion that had been considered to be CLIPPERS by neuroimaging. Identification of a BRAFV600E mutation allowed an ECD diagnosis and treatment with the specific BRAFV600E inhibitor vemurafenib, which resulted in a marked sustained clinical response. Case 3 was diagnosed as ECD after positive bone biopsy with typical foamy histiocytes. Six years later, there was massive dural involvement that showed RDD-like, BRAF-mutation-negative histiocytosis. These cases highlight the clinical and histologic overlap that can occur among these disorders.

The relationship of Epstein-Barr virus (EBV) has been well characterized with a wide range of lymphoproliferative lesions and lymphomas of B-cell, T-cell, and NK-cell origin. However, the association of EBV with mantle cell lymphoma (MCL) is exceedingly rare and not well established. We report a case of classic MCL which transformed to pleomorphic MCL after a clinical course of 19 years. Particularly, EBV infection was detected in the transformed high-grade pleomorphic MCL. Molecular and genetic analyses confirmed the clonal relationship between the original and transformed lymphomas. To the best of our knowledge, there has only been one case reported in 2003 which documented an EBV-associated high-grade transformation of MCL. Therefore, our case report further expanded the spectrum of EBV in the pathogenesis of B-cell lymphoma transformation.

Histiocytic and dendritic cell neoplasms are very rare, belonging to a group that share morphologic, immunophenotypic, and ultrastructural characteristics of mature histiocytic/dendritic neoplasms. Histiocytic and dendritic cell neoplasms may arise de novo or in association with B-cell, T-cell, or myeloid neoplasms. Recent molecular findings, particularly the discoveries of the mutations in the RAS-RAF-MEK-ERK pathway, have greatly advanced the diagnosis and treatment options. Histiocytic and dendritic cell neoplasms may closely resemble each other, non-hematopoietic neoplasms, and even reactive processes. Therefore, it is essential to understand the clinicopathologic characteristics, differential diagnoses, and pitfalls of each entity.

ObjectivesTo characterize the clinical and pathologic features of mantle cell lymphoma with mantle zone growth pattern (MCL-MZGP).MethodsThe clinicopathologic data from 35 cases of MCL-MZGP obtained in 12 centers were analyzed.ResultsThe patients with MCL-MZGP typically sought treatment at high clinical stages (81%). Intriguingly, 40% (14/35) of cases were incidentally noted. The lymph nodes with MCL-MZGP showed preserved architecture and expanded mantles containing lymphoma cells with classic or small cell cytology. MCL-MZGP was positive for BCL2 (96%, bright), CD5 (82%, moderate), cyclin D1 (100%), and SOX11 (89%). Clinically, our study revealed no significant difference in the overall survival between patients managed with observation alone and those who received chemotherapy.ConclusionsMCL-MZGP was often incidentally identified and resembled reactive mantles. Therefore, recognition of this unusual morphology emphasizes the utility of cyclin D1 immunostain in the cases with suspicious morphology. However, the clinical significance of these findings is still unclear.

Epstein-Barr virus (EBV) has been classified into two strains, EBV type 1 (EBV-1) and EBV type 2 (EBV-2) based on genetic variances and differences in transforming capacity. EBV-1 readily transforms B cells in culture while EBV-2 is poorly transforming. The differing abilities to immortalize B cells in vitro suggest that in vivo these viruses likely use alternative approaches to establish latency. Indeed, we recently reported that EBV-2 has a unique cell tropism for T cells, infecting T cells in culture and in healthy Kenyan infants, strongly suggesting that EBV-2 infection of T cells is a natural part of the EBV-2 life cycle. However, limitations of human studies hamper further investigation into how EBV-2 utilizes T cells. Therefore, BALB/c Rag2(null) IL2rγ(null) SIRPα humanized mice were utilized to develop an EBV-2 in vivo model. Infection of humanized mice with EBV-2 led to infection of both T and B cells, unlike infection with EBV-1, in which only B cells were infected. Gene expression analysis demonstrated that EBV-2 established a latency III infection with evidence of ongoing viral reactivation in both B and T cells. Importantly, EBV-2-infected mice developed tumors resembling diffuse large B cell lymphoma (DLBCL). These lymphomas had morphological features comparable to those of EBV-1-induced DLBCLs, developed at similar rates with equivalent frequencies, and expressed a latency III gene profile. Thus, despite the impaired ability of EBV-2 to immortalize B cells in vitro, EBV-2 efficiently induces lymphomagenesis in humanized mice. Further research utilizing this model will enhance our understanding of EBV-2 biology, the consequence of EBV infection of T cells, and the capacity of EBV-2 to drive lymphomagenesis. IMPORTANCE EBV is a well-established B cell-tropic virus. However, we have recently shown that the EBV type 2 (EBV-2) strain also infects primary T cells in culture and in healthy Kenyan children. This finding suggests that EBV-2, unlike the well-studied EBV-1 strain, utilizes the T cell compartment to persist. As EBV is human specific, studies to understand the role of T cells in EBV-2 persistence require an in vivo model. Thus, we developed an EBV-2 humanized mouse model, utilizing immunodeficient mice engrafted with human cord blood CD34(+) stem cells. Characterization of the EBV-2-infected humanized mice established that both T cells and B cells are infected by EBV-2 and that the majority of infected mice develop a B cell lymphoma resembling diffuse large B cell lymphoma. This new in vivo model can be utilized for studies to enhance our understanding of how EBV-2 infection of T cells contributes to persistence and lymphomagenesis.

Acute lymphoblastic leukemia (ALL) in infants

Histiocytic sarcoma (HS) is a rare malignant tumor, and in extraordinary circumstances it can be transdifferentiated from a low-grade B-cell lymphoma. In our report, a 62-year-old female was initially diagnosed with a low-grade follicular lymphoma, and 2 years later she presented with bilateral lung masses and lymphadenopathy. Fine needle aspiration (FNA) of the lung masses revealed solid nests of large pleomorphic epithelioid cells. By immunohistochemical studies, the tumor cells were positive for histiocytic markers (CD68 and CD163) and S100, supporting a diagnosis of HS with dendritic cell differentiation. Further fluorescence in situ hybridization (FISH) analyses detected IGH@/BCL2 rearrangement in both the previous follicular lymphoma and the current HS, which was highly suggestive of the clonal relationship between these two tumors. To the best of our knowledge, this is the first case of transformation of follicular lymphoma into HS diagnosed by FNA of lung masses.

Amyloid precursor-like protein 2 (APLP2) is aberrantly expressed in pancreatic cancer. Here we showed that APLP2 is increased in pancreatic cancer metastases, particularly in metastatic lesions found in the diaphragm and intestine. Examination of matched human primary tumor-liver metastasis pairs showed that 38.1% of the patients had positive APLP2 expression in both the primary tumor and the corresponding liver metastasis. Stable knock-down of APLP2 expression (with inducible shRNA) in pancreatic cancer cells reduced the ability of these cells to migrate and invade. Loss of APLP2 decreased cortical actin and increased intracellular actin filaments in pancreatic cancer cells. Down-regulation of APLP2 decreased the weight and metastasis of orthotopically transplanted pancreatic tumors in nude mice.

Mediastinal gray-zone lymphoma is intermediate between classic Hodgkin’s lymphoma and primary mediastinal B-cell lymphoma. Three patients whose disease had become refractory to chemotherapy had impressive responses to PD-1 blockade.

Extranodal NK/T-cell lymphoma (ENKTL) is a rare aggressive extranodal non-Hodgkin lymphoma (NHL) universally associated with Epstein-Barr virus (EBV). ENKTL most commonly occurs in non-elderly immune competent males in Asia and South America. A number of antecedent lymphoproliferative disorders (LPDs) have been described in Asian and South American patients, but the majority of Caucasian ENKTL patients have no known preceding LPD or underlying immunodeficiency. Other than EBV, no environmental or extrinsic factor has been implicated in oncogenesis. The precise mechanisms by which EBV infects NK or T cells and the virus’ role in the pathogenesis of ENKTL have not been fully deciphered. However, a number of recent discoveries including disturbances in cell signaling and mutations in tumor suppressor genes have been identified, which are providing insights into the pathogenesis of ENKTL. In this review, we highlight the molecular, viral, and genetic underpinnings of ENKTL and discuss potential therapeutic implications.

Extranodal NK/T cell lymphoma, nasal type (ENKTL-NT) is an aggressive extranodal non-Hodgkin lymphoma most commonly occurring in East Asia and Latin America but with increasing incidence in the United States. Data on epidemiology, disease presentation, and outcome for European and North American (“Western”) cases are very limited. We review published landmark clinical studies on ENKTL-NT in the West and report in detail recent data, including our institutional experience. We highlight key observations in its epidemiology, natural history, and trends in clinical management. In the USA, ENKTL-NT is more common among Asian Pacific Islanders (API) and Hispanics compared to non-Hispanic whites. Published studies indicate less heterogeneity in clinical presentation in Western ENKTL-NT compared to Asian patients. While there is variation in age at diagnosis, presence of antecedent lymphoproliferative disorders, and outcomes among racial/ethnic groups, the universal association of ENKTL-NT with EBV and the poor response of this neoplasm to anthracycline-based therapy is consistent across all geographic areas. Data on epidemiology, disease presentation, and clinical outcomes in mature T cell and NK cell (T/NK cell) neoplasms, including ENKTL-NT, in Europe and North America are very limited. As the classification and diagnostic characterization of the currently recognized T/NK cell lymphoma disease entities continue to evolve, gaps and inconsistencies in data reporting across different studies are being recognized. Despite these limitations, several studies from the USA suggest that the incidence of ENKTL-NT is higher in Asian Pacific Islanders (API) and non-white Hispanics and that outcomes may be worse in non-whites. However, the universal association of ENKTL-NT with Epstein-Barr virus (EBV) across all ethnic groups suggests a common pathogenesis. Given the overlap between the entities included in the category of T/NK cell neoplasms, there is a need to further define biological and clinical differences that may affect diagnosis, treatment, and outcome.

Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK LBCL) is a rare, aggressive subtype of diffuse large B-cell lymphoma with characteristic ALK rearrangements. Diagnosis of ALK LBCL can be challenging because of its rarity, unique morphologic characteristics, and unusual immunophenotypic features, which significantly overlap with other hematologic and nonhematologic neoplasms. The purpose of this study is to further explore the clinicopathologic features of ALK LBCL to ensure the awareness and accurate diagnosis of this entity. We retrospectively reviewed the data from 26 cases in our institutions and additional 108 cases from the literature. ALK LBCL typically occurred in the lymph nodes of young and middle-aged, immunocompetent patients. The medium age was 35 years with a male to female ratio of 3.5:1. Vast majority of cases showed immunoblastic and/or plasmablastic morphology. All cases expressed ALK protein with a cytoplasmic granular pattern in most of them. Common B-cell markers (CD20, CD79a, and PAX5) were typically negative, but the tumor cells mostly expressed 2 B-cell transcriptional factors, BOB1 and OCT2. The 5-year overall survival (OS) was 34%, and the median survival was 1.83 years. In patients with stage III/IV disease, the 5-year OS was only 8%. Moreover, patients below 35 years of age had a significantly better OS than those aged 35 years or above.

Aims Rare cases of B cell lymphomas do not express conventional B cell markers (CD20, CD79a and PAX5), and these types of lymphomas include anaplastic lymphoma kinase (ALK)-positive large B cell lymphoma, plasmablastic lymphoma, primary effusion lymphoma and the solid variant of primary effusion lymphoma, extracavitary human herpesvirus 8 (HHV8)-positive large B cell lymphoma. Establishing accurate diagnoses of these B cell lymphomas can be challenging, and often requires a large panel of immunohistochemical stains, molecular assays and cytogenetic studies. B cell-specific transcription factors, Oct2 and Bob1, have been shown to be expressed consistently in most, if not all, B cell lymphomas, and therefore we investigated the utility of Oct2 and Bob1 immunohistochemistry in lineage determination of the aforementioned B cell lymphomas. Methods and results We selected 34 cases of previously diagnosed B cell lymphomas with no or weak expression of CD20, CD79a and PAX5. Oct2 and Bob1 were positive in 74% (25 of 34) and 85% (29 of 34) of the cases, respectively. When we combined the results of these two immunostains, 94% (32 of 34) cases expressed at least one of these two markers. We also included 51 control cases of non-B cell neoplasms, and none of them expressed either Oct2 or Bob1. Conclusions Oct2 and Bob1 are very reliable in determining B cell lineage in the absence of expression of other pan-B cell markers, and it should provide great diagnostic benefit to include them both in a panel of immunohistochemistry to assess undifferentiated malignant neoplasms.

IgG4-related lymphadenopathy (IgG4-LAD) is newly described entity, which may occur before, during or after diagnosis of extranodal IgG4-related disease. It is important to recognize IgG4-LAD, especially in cases with lymphadenopathy as the initial presentation, so that the patients can receive prompt treatment. However, it can be challenging to formulate a final diagnosis since IgG4-LAD displays a broad morphologic spectrum. Moreover, morphologic changes alone are not sufficient for diagnosis of IgG4-LAD, and an accurate diagnosis has to take into account of the overall clinical presentations and laboratory studies. Currently, it is not very clear when pathologists should consider workup for potential IgG4-LAD based on the histologic features. Particularly, for some pathologists, it is not certain how to render the diagnosis in reactive lymph nodes with markedly increased IgG4 + cells. In this review, we will attempt to summarize the major clinicopathologic features of IgG4-LAD and its variants, differential diagnoses, and algorithms to establish an accurate diagnosis.

In some cellular systems, particularly neurons, amyloid precursor-like protein 2 (APLP2), and its highly homologous family member amyloid precursor protein (APP), have been linked to cellular growth. APLP2 and APP undergo regulated intramembrane proteolysis to produce C-terminal fragments. In this study, we found comprehensive expression of APLP2 C-terminal fragments in a panel of pancreatic cancer cell lines; however, APP C-terminal fragments were notably limited to the BxPC3 cell line. Extensive glycosaminoglycan modification on APLP2 was also found in the majority of pancreatic cancer cell lines. Glycosaminoglycan-modified and -unmodified APLP2, and particularly APLP2 C-terminal fragments, also demonstrated increased expression in oncogene-transformed pancreatic ductal cells. Additionally, elevated APLP2 levels were confirmed in human pancreatic cancer tissue. Downregulation of APLP2 and APP expression, alone or in combination, caused a decrease in the growth of a pancreatic cancer cell line with representatively low APP C-terminal fragment expression, the S2-013 cell line. Furthermore, we found that treatment with β-secretase inhibitors to block formation of APLP2 C-terminal fragments decreased the growth and viability of S2-013 cells, without affecting the survival of a non-transformed pancreatic ductal cell line. In conclusion, our studies demonstrate that abundant APLP2, but not APP, C-terminal fragment expression is conserved in pancreatic cancer cell lines; however, APP and APLP2 equally regulated the growth of S2-013 pancreatic cancer cells. Chiefly, our discoveries establish a role for APLP2 in the growth of pancreatic cancer cells and show that inhibitors preventing APLP2 cleavage reduce the viability of pancreatic cancer cells.

Aneurysmal bone cyst is a rapidly growing and locally aggressive lesion that commonly affects children and young adults. Initially regarded as a reactive process, primary aneurysmal bone cyst is now widely accepted as a neoplasm owing to recent findings of recurrent clonal chromosomal alterations, mostly t(16;17)(q22;p13). However, other infrequent chromosomal rearrangements have also been reported. Giant cell reparative granuloma, previously regarded as a nonneoplastic process and histologically indistinguishable from the solid variant of aneurysmal bone cyst, is frequently seen in the gnathic bones and the short tubular bones of the hands and feet. Here we present such a case of giant cell reparative granuloma (solid aneurysmal bone cyst) in the finger of a 63-year-old white man. Cytogenetic analysis revealed a novel alteration involving a reciprocal translocation between 6q and 13q, with a karyotype of 46,XY,t(6;13)(q15;q34),del(20)(q13.1).

Summary Pleomorphic hyalinizing angiectatic tumor of soft parts is a recently recognized, low-grade mesenchymal neoplasm of uncertain lineage. It is characterized by clusters of ectatic, fibrin-lined, thin-walled vessels surrounded by pleomorphic but mitotically inert spindled cells with frequent intranuclear inclusions and a variable inflammatory component. Here, we report a case of recurrent pleomorphic hyalinizing angiectatic tumor in a 37-year-old white woman. Touch imprint cytologic analysis revealed oval and spindled cells with fine chromatin, occasional prominent intranuclear inclusions, and intracytoplasmic pigment. The histologic features of the cells constituting the bulk of tumor were those characteristic of a putative precursor lesion ("early pleomorphic hyalinizing angiectatic tumor") as well as another recently described entity known as hemosiderotic fibrohistiocytic lipomatous lesion. Cytogenetic analysis revealed 2 unbalanced translocations involving chromosomes 1 and 3 and chromosomes 1 and 10, with a karyotype of 45,XX,der(1)t(1;3)(p31;q12),-3,der(10)t(1;10)(p31;q25)[11]/46,XX[4], thus suggesting that this disease is neoplastic. The controversies in classification of these lesions are also discussed.

7551Background: Pathologic grading of FL (1, 2, 3A, 3B; based on increasing number of centroblasts) is prognostic and predictive. FL 3B is treated similarly to aggressive lymphomas with rituximab a...

Histiocytic sarcoma (HS) is a rare malignant tumor, and in extraordinary circumstances it can be transdifferentiated from a low-grade B-cell lymphoma. In our report, a 62-year-old female was initially diagnosed with a low-grade follicular lymphoma, and 2 years later she presented with bilateral lung masses and lymphadenopathy. Fine needle aspiration (FNA) of the lung masses revealed solid nests of large pleomorphic epithelioid cells. By immunohistochemical studies, the tumor cells were positive for histiocytic markers (CD68 and CD163) and S100, supporting a diagnosis of HS with dendritic cell differentiation. Further fluorescence in situ hybridization (FISH) analyses detected IGH@/BCL2 rearrangement in both the previous follicular lymphoma and the current HS, which was highly suggestive of the clonal relationship between these two tumors. To the best of our knowledge, this is the first case of transformation of follicular lymphoma into HS diagnosed by FNA of lung masses.

We sought to determine whether identification of poor-risk subgroups of diffuse large B-cell lymphoma (DLBCL) using immunohistochemical stains would have practical utility with regard to prognosis and therapeutic decisions. Tissue microarray blocks were created using replicate samples of formalin-fixed, paraffin-embedded tissue from 200 cases of de novo DLBCL. The sections were stained with antibodies to proteins that are expressed by activated or proliferating B cells including MUM1, FOXP1, bcl-2, survivin, protein kinase C-beta (PKC-beta), cyclin D2, cyclin D3, and Ki-67. In univariate analysis, tumor expression of cyclin D2 (P = 0.025) or PKC-beta (P = 0.015) was associated with a worse overall survival, whereas none of the other markers was predictive of overall survival. Patients with DLBCL that expressed either cyclin D2 or PKC-beta had a 5-year overall survival of only 30% as compared to 52% for those who were negative for both markers (P = 0.0019). In multivariate analysis, the expression of cyclin D2 or PKC-beta was an independent predictor of poor overall survival (P = 0.035). Cyclin D2 and PKC-beta expression will be useful in designing a 'biological prognostic index' for patients with DLBCL.

Background : Post Transplant Lymphoproliferative disorder (PTLD) represents a distinct and rare complication following solid organ transplantation (SOT). Insight into the biology of this disorder is limited to retrospective reviews and case series. In one of the first reports for post-transplant Diffuse Large B cell Lymphoma (PT-DLBCL) cases, we demonstrated a higher incidence and improved outcomes in PT-DLBCL non-germinal center B-cell (non-GCB) subtype compared to PT-DLBCL germinal center B-cell (GCB) Subtype. Published data suggests immunocompetent DLBCL non-GCB subtypes are less common and fare worse than immunocompetent GCB DLBCL. The reason for this unexpected finding in our PT-DLBCL pts is not fully understood. Recently Kiyasu and colleagues demonstrated that PD-L1 overexpression was significantly associated with non-GCB DLBCL, EBV virus positivity and poor prognosis in immunocompetent DLBCL samples. Therefore based on this we hypothesized that PT-DLBCL non-GCB subtype may have negative PD-L1 overexpression thus possibly accounting for improved outcomes compared to their immunocompetent counterparts. Hence we sought to test PD-L1 expression in our samples with PT-DLBCL. Methods: With IRB approval, we retrospectively identified PT- DLBCL patients treated at the University of Colorado between Jan 1989 to April 2015. We retrieved formalin fixed paraffin embedded PT-DLBCL tissue specimens and determined cell of origin by the Hans Algorithm. We assessed PD-L1 expression by immunohistochemistry. PD-L1 positive PT-DLBCL was defined as 30% of more of the lymphoma cells showing distinct membranous and or cytoplasmic staining. In addition EBER-ISH was performed to assess EBV status. Results: 86 adult SOT pts with PTLD were treated at our institution. 75 of 86 pts (87%) had monomorphic histology. Among monomorphic PTLD, 64% (48 of 75) had DLBCL. The median age at transplantation was 49.5 yrs (5-74 yrs). Median time from SOT to PTLD was 37 mos (1.4-499). The most common transplanted organ included kidney (40%), liver (38%), lung (13%) and heart (9%). 31% had early PTLD (12mos of SOT). 60% were EBV positive. 77% with early PTLD and 49% with late PTLD were EBV positive. Due to a paucity of archived tissue blocks, IHC staining was applied to 32/48 samples with DLBCL. Non-GCB subtype was identified in 75% (24/32) samples and GCB subtype in 25% (8/32) samples. Of the 48 pts with PT-DLBCL histology, PD-L1 stain was performed on 18 samples. Of the 18 PT-DLBCL samples, 77% (14/18) had non-GCB subtype and 16% (3/18) had GCB subtype. PD-L1 expression was negative in 78% (11/14) and positive in 22% (3/14) of non-GCB DLBCL samples. PD-L1 expression was negative in 100% (3/3) of GCB DLBCL samples. The sample size was too small to effectively describe the survival experience of pt subsets. Using Fisher's exact test we found no evidence to support an association between EBV Status and PDL1 expression (p-value 0.316). Conclusions: We previously reported in our consecutive series of PTLD after SOT an increased incidence and improved survival in pts with PT-DLBCL non-GCB subtype (ASH 2015) compared to PT-DLBCL GCB subtype. The reason for this is not fully understood. However, our limited series reveals that a majority of pts with PT- DLBCL non-GCB subtype was negative for PD-L1 overexpression. This might explain the improved outcomes in the PT-DLBCL non-GCB population. Despite a small sample size it is also interesting to note that 100% pts with PT-DLBCL GCB subtype were negative for PD-L1 overexpression. In the era of immunotherapy further studies in larger patient cohorts are warranted in order to understand the unique biology and outcomes of PT-DLBCL since it may have therapeutic implications. Disclosures Pollyea: Celgene: Other: advisory board, Research Funding; Ariad: Other: advisory board; Alexion: Other: advisory board; Pfizer: Other: advisory board, Research Funding; Glycomimetics: Other: DSMB member. Kamdar:Seattle Genetics: Speakers Bureau.