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Breast implant-associated anaplastic large cell lymphoma (ALCL) is a distinctive type of T-cell lymphoma that arises around textured-surface breast implants. In a subset of patients, this disease can involve surrounding tissues, spread to regional lymph nodes, and rarely metastasize to distant sites. The aim of this study was to assess sequential pathologic specimens from patients with breast implant-associated ALCL to better understand the natural history of early-stage disease. To achieve this goal, we searched our files for patients who had breast implant-associated ALCL and who had undergone earlier surgical intervention with assessment of biopsy or cytologic specimens. We then focused on the patient subset in whom a definitive diagnosis was not established, and patients did not receive current standard-of-care therapy at that time. We identified a study group of ten patients with breast implant-associated ALCL in whom pathologic specimens were collected 0.5 to 4 years before a definitive diagnosis was established. A comparison of these serial biopsy specimens showed persistent disease without change in pathologic stage in three patients, progression in five patients, and persistence versus progression in two patients. Eventually, six patients underwent implant removal with complete capsulectomy and four underwent partial capsulectomy. Seven patients also received chemotherapy because of invasive disease, three of whom also received radiation therapy, two brentuximab vedotin after chemotherapy failure, and one allogeneic stem cell transplant. Eight patients achieved complete remission and two had partial remission after definitive therapy. At time of last follow-up, six patients were alive without disease, one had evidence of disease, one died of disease, and two patients died of unrelated cancers. In summary, this analysis of sequential specimens from patients with breast implant-associated ALCL suggests these neoplasms persist or progress over time if not treated with standard-of-care therapy.

Germline DDX41 variants in myeloid neoplasms (MNs) are not uncommon, and we explored the prevalence and characterized the clinical and pathologic features in a cohort of 3132 unrelated adult MN patients. By targeted next-generation sequencing, we identified 28 patients (20 men and 8 women) with pathogenic germline DDX41 variants who developed acute myeloid leukemia (AML), in which only 3 (11%) had a family history (FH) of MNs. A subacute clinical course of cytopenia (mean duration of 11.2 months, range 0-72 months) prior to the initial AML diagnosis was accompanied by a low blast count (median at 30%, range 20-70%) in hypocellular marrows (93% of all patients), in vast contrast to the typical proliferative subtypes of AML in the elderly. Most patients had a normal karyotype (75%) and acquired a second DDX41 variant (69%). A favorable overall survival (OS) was observed in comparison to that of common subtypes of AML with wild-type DDX41 in age-matched patients. Our study demonstrated that the frequent germline pathogenic DDX41 variants characterized a clinically distinct AML entity. Features characteristic of DDX41-mutated AML include male predominance, often lack of FH, indolent course, low proliferative potential, frequent somatic DDX41 variants, and a favorable OS.

Primary cutaneous anaplastic large-cell lymphoma and breast implant-associated ALCL (BIA-ALCL) are rare subtypes of anaplastic lymphoma kinase (ALK)-negative ALCLs originating from skin and breast implants, respectively. Herein, we report a unique case of cutaneous ALK-negative ALCL occurring in the skin of left medial breast from a patient with multiple rounds of bilateral breast implants and a history of breast carcinoma. The lymphoma cells are entirely confined to the lymphatic channels in the dermis, and the patient has no other areas of skin abnormality, no lymphadenopathy, peri-implant fluid accumulation, or masses from the bilateral capsules of implants. The differential diagnosis and its relationship with breast implants are further explored.

Monomorphic posttransplant lymphoproliferative disorders have been defined as lymphoid or plasmacytic proliferations that fulfill criteria for one of the B-cell or T/NK-cell neoplasms recognized in immunocompetent hosts in the current WHO Classification. Low-grade B-cell neoplasms have historically been excluded from this category, although rare reports of marginal zone lymphoma (MZL) have been described. We report 9 cases of posttransplant Epstein-Barr virus-negative MZL, all arising in solid organ transplant recipients (4 renal, 3 liver, 1 cardiac, and 1 liver, pancreas, and small bowel). Seven were extranodal MZL of mucosa-associated lymphoid tissue type, all of which had gastrointestinal involvement (4 colon, 1 duodenum, 1 stomach, and 1 oropharynx/base of tongue). Notably, the preferential involvement of intestine distinguishes posttransplant extranodal MZL from sporadic cases. Immunoglobulin light-chain restriction was seen in all cases, with polymerase chain reaction showing a monoclonal pattern in 7 of 8 cases with successful amplification of polymerase chain reaction products. A clonally unrelated recurrence was seen in one case. Next-generation sequencing identified recurrent mutations previously reported in MZL in 3/5 cases. MZL was diagnosed at least 1 year after solid organ transplant (median time to presentation, 84 mo; range, 13 to 108 mo). The median age was 44 (range, 9 to 73 y); the male: female ratio was 5:4. The mean follow-up was 33.4 months, with an indolent clinical course observed. A subset responded to reduction in immunosuppression and anti-CD20 therapy alone. These data support the designation of Epstein-Barr virus-negative MZL as an uncommon form of monomorphic posttransplant lymphoproliferative disorders.

Primary mediastinal (thymic) large B-cell lymphoma (PMBL) is a subtype of uncommon aggressive large B-cell lymphomas primarily occurring in mediastinum although rare cases with non-thymic type of PMBL have been reported. Typical PMBL has characteristic clinical, morphological, and immunophenotypic features which the pathologists use as diagnostic paradigm in routine practice. However, the diagnosis can be occasionally challenging due to the overlapping clinicopathologic features with other lymphomas, among which are nodular sclerosis classic Hodgkin lymphoma, systemic diffuse large B-cell lymphoma (DLBCL) involving mediastinum, and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classic Hodgkin lymphoma (gray zone lymphoma). Recent depictions of the characteristic genetic/ molecular aberrations and unique gene expression profiling in PMBL have provided a robust tool to significantly improve the diagnostic accuracy. In addition, the progresses in understanding the pathogenesis of PMBL have paved the way discovering novel therapeutic agents for patients with refractory/relapsed disease.

Objectives Castleman disease (CD) is a heterogeneous group of disorders involving systemic inflammation and lymphoproliferation. Recently, clonal mutations have been identified in unitcentric CD (UCD) and idiopathic multicentric CD (iMCD), suggesting a potential underlying neoplastic process. Methods Patients with UCD or iMCD with next generation sequencing (NGS) data on tissue DNA and/or circulating tumor DNA (ctDNA) were included. Results Five patients were included, 4 with iMCD and 1 with UCD. Four patients (80%) were women; median age was 40 years. Three of five patients (60%) had ≥1 clonal mutation detected on biopsy among the genes included in the panel. One patient with iMCD had a 14q32-1p35 rearrangement and a der(1)dup(1)(q42q21)del(1)(q42) (1q21 being IL-6R locus) on karyotype. This patient also had a NF1 K2459fs alteration on ctDNA (0.3%). Another patient with iMCD had a KDM5C Q836* mutation, and one patient with UCD had a TNS3-ALK fusion but no ALK expression by immunohistochemistry. Conclusions We report 4 novel somatic alterations found in patients with UCD or iMCD. The 1q21 locus contains IL-6R, and duplication of this locus may increase IL-6 expression. These findings suggest that a clonal process may be responsible for the inflammatory phenotype in some patients with UCD and iMCD.

High‐throughput single‐cell cytometry technologies have significantly improved our understanding of cellular phenotypes to support translational research and the clinical diagnosis of hematological and immunological diseases. However, subjective and ad hoc manual gating analysis does not adequately handle the increasing volume and heterogeneity of cytometry data for optimal diagnosis. Prior work has shown that machine learning can be applied to classify cytometry samples effectively. However, many of the machine learning classification results are either difficult to interpret without using characteristics of cell populations to make the classification, or suboptimal due to the use of inaccurate cell population characteristics derived from gating boundaries. To date, little has been done to optimize both the gating boundaries and the diagnostic accuracy simultaneously. In this work, we describe a fully discriminative machine learning approach that can simultaneously learn feature representations (e.g., combinations of coordinates of gating boundaries) and classifier parameters for optimizing clinical diagnosis from cytometry measurements. The approach starts from an initial gating position and then refines the position of the gating boundaries by gradient descent until a set of globally‐optimized gates across different samples are achieved. The learning procedure is constrained by regularization terms encoding domain knowledge that encourage the algorithm to seek interpretable results. We evaluate the proposed approach using both simulated and real data, producing classification results on par with those generated via human expertise, in terms of both the positions of the gating boundaries and the diagnostic accuracy. © 2019 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.

Context.—Recent advances in comprehensive genomic profiling by next-generation sequencing have uncovered the genomic alterations at the molecular level for many types of tumors; as such, numerous small specific molecules that target these alterations have been developed and widely used in the management of these cancers.Objective.—To provide a concise molecular genomic update in solid, bone and soft tissue tumors, hematopoietic as well as lymphoid malignancies; discuss its clinical applications; and familiarize practicing pathologists with the emerging cancer biomarkers and their diagnostic utilities.Data Sources.—This review is based on the National Comprehensive Cancer Network guidelines and peer-reviewed English literature.Conclusions.—Tumor-specific biomarkers and molecular/genomic alterations, including pan-cancer markers, have been significantly expanded in the past decade thanks to large-scale high-throughput technologies and will continue to emerge in the future. These biomarkers can be of great value in diagnosis, prognosis, and/or targeted therapy/treatment. Familiarization with these emerging and ever-changing tumor biomarkers will undoubtedly aid pathologists in making accurate and state-of-the-art diagnoses and enable them to be more actively involved in the care of cancer patients.

Since the first reported case in 1997, over 600 women with breast implant-associated anaplastic large cell lymphoma (BI ALCL) have been reported. BI ALCL is a CD30-positive T-cell lymphoma that carries clonal T-cell receptor gene rearrangements, and a subset of cases harbors mutations in the JAK-STAT signaling pathway. Rarely, other histologic types of lymphoma have been reported in association with breast implants, including fewer than 10 cases of B-cell origin. Here, we describe three additional patients with B-cell lymphoma occurring around breast implants. Two of these patients developed extranodal marginal zone lymphoma in the peri-implant capsule, one of which had a concurrent ALCL within the superficial lining of the capsule. The third patient presented with diffuse large B-cell lymphoma inside the breast parenchyma surrounding her implant. Determining the etiology and risk factors for the development of B-cell lymphomas associated with breast implants remains challenging, given the wide spectrum of histologic features and the rarity of these neoplasms. Ultimately, we document three new cases of B-cell lymphoma arising around breast implants and highlight their clinical and pathologic features in order to expand our understanding of this rare disease presentation.

While the majority of NK/T-cell neoplasms are unfavorable in clinical outcome, a few pathologic variants demonstrate relatively indolent behavior. These include primarily four types of tissue-based T-cell or NK-cell lymphoproliferative disorders and two leukemic forms of T-cell or NK-cell lymphoproliferative disorder. The diagnostic criteria and other clinicopathologic features of these entities are discussed as question and answer format.

InGaN/GaN multiquantum well (MQW) structures have been grown on cone-shaped patterned sapphire substrates (CPSS) by metalorganic chemical vapor deposition (MOCVD). From the transmission electron microscopy (TEM) results, we found that most of the threading dislocations (TDs) in the trench region of the CPSS were bent by lateral growth mode. Also the staircase-like TDs were observed near the slant region of the cone pattern, they converged at the slope of the cone patterned region by staircase-upward propagation, which seems to effectively prevent TDs from vertical propagation in the trench region. The associated dislocation runs up into the overgrown GaN layer and MQW, and some (a+c) dislocations were shown to decompose inside the multi-quantum well, giving rise to a misfit segment in the c-plane and a V-shape defect. From cross-sectional TEM, we found that all V defects are not always connected with TDs at their bottom, some V defects are generated from the stacking mismatch boundaries induced by stacking faults which are formed within the MQW due to the strain relaxation.

Key Points Brentuximab vedotin is active in primary effusion lymphoma, a rare CD30-positive lymphoma with an extremely poor prognosis.

In 2018, the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) updated the guidelines for diagnosis, indications for treatment, response assessment, and supportive management of patients with chronic lymphocytic leukemia. Included were definitions for response, which incorporated consideration of the significance of minimal residual disease. Here we discuss the clinical significance of complete response or partial response, as defined in the 2018 iwCLL guidelines, and the relative value of assessing for minimal residual disease.

Thoracic extramedullary hematopoiesis (EMH) is a rare manifestation in patients with myeloproliferative neoplasm. A 76-year-old woman with a long-standing history of polycythemia vera presented with a 2-month history of worsening dyspnea and left-sided wheezing. A chest computed tomography showed an ill-defined soft tissue mass encasing the left mainstem bronchus causing airway obstruction, associated with paratracheal and paraesophageal lymphadenopathy. Endobronchial ultrasound-guided fine needle aspiration of the soft tissue mass and mediastinoscopy with excisional biopsy of a paratracheal lymph node demonstrated EMH with increased myeloid blasts. A bone marrow biopsy confirmed postpolycythemic myelofibrosis consistent with progression of polycythemia vera to myelofibrosis. We describe the bronchoscopic management of a case of EMH presenting as a mediastinal mass, mimicking malignancy.

Blue light-emitting diodes (LEDs) with an InGaN multi-quantum well (MQW) structure were fabricated on cone-shaped patterned sapphire substrate (PSS) using a single growth process of metal organic chemical vapor deposition (MOCVD). The PSS was proved to be an efficient method to decrease the threading dislocation (TD) density in GaN epifilm with the lateral growth mode on PSS. The LED designed on PSS increased the electroluminescene (EL) intensity. The internal quantum efficiency is increased by reducing the dislocation density, and light extraction efficiency is also enhanced owing to PSS.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. It is characterized by the accumulation of CD19+/CD5+ lymphocytes and can have variable outcomes. Richter syndrome (RS) is a lethal complication in CLL patients that results in aggressive B-cell lymphomas, and there are no tests to predict its occurrence. Because alterations in microRNA expression can predict the development and progression of several cancers, we investigated whether dysregulation of specific microRNAs can predict RS in CLL patients. Thus, we compared microRNA expression levels in samples from 49 CLL patients who later developed RS with samples from 59 CLL patients who did not. We found that high expression of miR-125a-5p or low expression of miR-34a-5p can predict ∼50% of RS with a false positive rate of ∼9%. We found that CLL patients predicted to develop RS show either an increase of miR-125a-5p expression (∼20-fold) or a decrease of miR-34a-5p expression (∼21-fold) compared with CLL patients that are not predicted to develop RS. Thus, miR-125a-5p and miR-34a-5p can be valuable predictor markers of RS and have the potential to provide physicians with information that can indicate the best therapeutic strategy for CLL patients.

A 52 year-old man with Erdheim-Chester Disease (ECD) (a non-Langerhans polyostotic sclerosing histiocytosis) had next-generation sequencing (NGS) performed as part of his diagnostic workup. In addition to the tissue BRAF V600E mutation that is found in over 50% of ECD cases, he was also found to have a JAK2 V617F alteration in cell-free circulating tumor DNA (ctDNA) (liquid biopsy). The latter was thought to be an “incidental” finding, perhaps due to clonal hematopoiesis (though this usually occurs in older individuals), as his blood counts were normal and he had no splenomegaly. Approximately 13 months after the ctDNA test showing JAK2 V617F, he developed anemia, thrombocytopenia, and splenomegaly. Marrow biopsy then showed megakaryocytic atypia and markedly increased marrow fibrosis, consistent with WHO grade 2 of 3 myelofibrosis. Therefore, the patient was determined to have ECD with a typical BRAF V600E mutation, as well as primary myelofibrosis, with the latter diagnosis manifesting clinically over one year after the JAK2 V617F was first detected in ctDNA. He recently was started on the JAK2 inhibitor ruxolitinib. This case demonstrates that genomic alterations detected by liquid biopsy for evaluation of specific malignancies already present may serve as an early harbinger of hematological disease.

Author(s): Wang, Huan-You; McMahon, Caitlin; Ali, Siraj M; Young, Lauren E; Yekezare, Somaye; Ross, Jeffrey S; Ball, Edward D

[Figure][1] Cervical lymph node (LN) dissection for squamous cell carcinoma was performed on a 69-year-old man in whom chronic lymphocytic leukemia (CLL) was diagnosed in 2004. Fluorescence in situ hybridization determined that the CLL had an ATM deletion. Prior to surgery, the patient

[Figure][1] A 52-year-old man with history of AIDS, rectal Kaposi sarcoma, and multicentric Castleman disease was found to have diffuse lymphadenopathy, bilateral pleural effusions, and ascites. Cytology smears of the pleural effusion (panel A; Diff-Quik) showed numerous large atypical

Background Patients infected with HIV have a significantly increased risk of developing non–Hodgkin lymphomas despite the widespread use of HAART. To investigate mTOR pathway activity in acquired immunodeficiency syndrome (AIDS) related diffuse large B-cell lymphoma AR-DLBCL, we used immunohistochemistry to examine the presence of the phosphorylated 70 ribosomal S6 protein-kinase (p70S6K), an extensively studied effector of mTOR Complex 1 (mTORC1) and the phosphorylated phosphatase and tensin homolog (pPTEN), a negative regulator of mTORC1 pathway. Materials and methods We evaluated tissue samples from 126 patients with AR-DLBCL. Among them, 98 samples were from tissue microarrays (TMAs) supplied by the Aids and Cancer Specimen Resource (ACSR), the remaining 28 samples were from cases diagnosed and treated at the University of California, San Diego (UCSD). The presence of p70S6K was evaluated with two antibodies directed against the combined epitopes Ser235/236 and Ser240/244, respectively; and additional monoclonal anti-bodies were used to identify pPTEN and phosphorylated proline-rich Akt substrate of 40kDa (pPRAS40). The degree of intensity and percentage of cells positive for p70S6K and pPTEN were assessed in all the samples. In addition, a subgroup of 28 patients from UCSD was studied to assess the presence of pPRAS40, an insulin-regulated activator of the mTORC1. The expression of each of these markers was correlated with clinical and histopathologic features. Results The majority of the patients evaluated were males (88%); only two cases (1.6%) were older than 65 years of age. We found high levels of both p70S6K-paired epitopes studied, 48% positivity against Ser235/236 (44% in ACSR and 64% in UCSD group), and 86% positivity against Ser240/244 (82% in ACSR and 100% in UCSD group). We observed more positive cells and stronger intensity with epitope Ser240/244 in comparison to Ser235/236 (p

Classical Hodgkin lymphoma (CHL) is recognized as a B-cell neoplasm arising from germinal center or postgerminal center B-cells. The hallmark of CHL is the presence of CD30 (+) Hodgkin and Reed-Sternberg (HRS) cells with dim expression of PAX5. Nearly all of the HRS cells are positive for PAX5. However, a small minority of HRS cells may lack PAX5 expression, which can cause a diagnostic dilemma. Herein we describe two cases of PAX5-negative CHL and review of the English literature on this very rare entity. It is crucial to be aware of this phenomenon, which in some cases may lead to misdiagnosis and may ultimately adversely affect patient’s management.

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.

Although rare, hairy cell leukemia (HCL) can be positive for CD10; thus, differential diagnosis of CD10(þ) small mature B-cell lymphoma should expand from follicular lymphoma and Burkitt lymphoma to include HCL. Interpretation of immunophenotype revealed by flow cytometry always has to be correlated with cytomorphology to avoid misdiagnosis. Although rare, HCL can involve extramedullary tissues especially lymph nodes; thus, when a fine-needle aspiration is performed on a lymph node, be aware of nodal involvement by HCL. A multimodality approach including clinical presentation, imaging, flow cytometry, and cytomorphologic assessment is needed for working up B-cell lymphoma.

Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) are characterized by the overproduction of mature blood cells and variable bone marrow fibrosis. MPNs attributed to dysregulation of the Janus kinase 2 (JAK2) pathway include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Somatic mutations in JAK2, thrombopoietin receptor (MPL), and calreticulin (CALR) have been identified as driver mutations with direct or upstream upregulation of JAK2. CALR mutations are the most recently described, with the two most common mutations being a 52-base pair (bp) deletion (type 1) or 5 bp insertion (type2) in exon 9. Studies have shown a prognostic advantage to type1/type 1 like CALR driven MPNs over JAK2, MPL, and type2 CALR driven MPNs. Rarer CALR exon 9 mutations have also been identified in presumed MPN patients negative for JAK2 and MPL mutations. In these cases variable predicted changes to the CALR protein have resulted in speculative interpretations as to their relevance in the diagnosis of a suspected MPN. Here we report a patient with a longstanding history of myelofibrosis, thrombocytosis, and anemia, eventually determined to have an in-frame presumed germline (due to variant fraction and identification in the patient's child) CALR mutation downstream of a somatic type 1 CALR mutation. The overall compounded alterations generate a type 1 like mutation previously not described (to the best of our knowledge) in the literature. The patient is a 70-year old female noted to be persistently anemic all her life. While a bone marrow assessment was recommended early in life, the patient declined workup until a marrow biopsy was eventually performed at age 50. The biopsy reportedly showed mild marrow fibrosis and the patient was trailed on erythropoietin for her anemia with little benefit. At age 59 the patient was noted with thrombocytosis (478 X 109/L) and mild splenomegaly. Repeat marrow biopsy showed hypercellular marrow, marked fibrosis (WHO grade 3/3), and megakaryocyte clustering. JAK2 was noted to not be mutated. Over the next decade the patient developed symptomatic splenomegly and continued to be anemic with eventual intermittent transfusion requirement at age 65, pushing her risk to DIPPS-plus intermediate-2. During this period successive treatments included Revlimid, trial sonic hedgehog (shh) inhibitor, and JAK2 inhibitors with intervening multiyear long spans without treatment. Marrow fibrosis over this time was predominantly unchanged on the various therapies but symptomatic splenomegaly decreased on shh and JAK2 inhibitors. At present the patient requires intermittent transfusions and is on a JAK2 inhibitor. Recent NGS testing of marrow aspirate identified an in-frame presumed germline CALR mutation downstream of a compound somatic type 1 CALR mutation. A high molecular risk ASXL1 mutation was also identified. The in-frame CALR mutation results in a 9bp in frame deletion (c.1191_1199del, p.398_400delGluGluAsp), which has been reported at least 10 times in the literature. The various reports have one event mentioned as being presumably germline and non-pathogenic, while the other reports are equivocal to presumed pathogenic in light of negative JAK2 and MPL mutations in patients with clinical suspicion for a MPN. At our institution we have identified 4 instances of this 9bp deletion, 3 show allele fractions suggestive of being germline and 1 case with an allele fraction consistent with being a somatic mutation. In one germline case the patient also had a JAK2 V617F mutation and a diagnosis of a MPN. The other presumed germline case was found in an offspring of the patient described in this report and currently shows no signs of a MPN. The presumed somatic 9bp deletion was seen in patient with a hypocellular marrow myelodysplastic syndrome, found to also have a TET2 mutation and normal karyotype. While in-frame CALR exon 9 mutations are rare and predominantly considered germline non-pathogenic polymorphisms, there may be value in reporting such events in the context of patients with myeloid neoplasms as to not miss possible disease modifying mutations which may become apparent when aggregating multi-institution data sets. The patient highlighted in this report exhibits a strikingly long and relatively indolent disease course, notably despite an adverse prognostic risk category and high molecular risk mutation. Disclosures No relevant conflicts of interest to declare.

Recurring chromosome abnormalities are frequent events in cancer and are especially prevalent in hematologic neoplasms. Somatic heterozygous deletions on chromosome 20q are detected in a variety of hematopoietic malignancies including myelodysplastic syndrome (MDS), classical myeloproliferative neoplasm (MPN), MDS/MPN overlap disorders such as chronic myelomonocytic leukemia (CMML), and acute leukemias. Del(20q) is especially prevalent in MPN patients (~10-15%), where it is the most commonly detected cytogenetic abnormality associated with primary myelofibrosis (PMF) and post-polycythemia vera myelofibrosis (MF). This suggests that heterozygous loss of genes in the del(20q) common deleted region (CDR) may contribute to adverse MPN progression. Despite these observations, relatively few genes located within the CDR have been unambiguously implicated, highlighting a significant need for further investigation. To identify genes that may play an important role in the biology of del(20q)-associated malignancies we utilized a published gene expression dataset of bone-marrow derived CD34+ cells from MDS patients and healthy controls (Gerstung et al, 2015). Comparison of the patients harboring del(20q) to healthy controls revealed STK4 (encoding Hippo kinase MST1) to be the most significantly downregulated gene (mean: 3.5-fold) among those located within the chromosome 20q CDR. We therefore set out to assess the role of Hippo kinase inactivation in hematologic malignancy using conditional gene inactivation in mice. We found that complete inactivation of both Hippo kinases (Stk4 and Stk3) within the hematopoietic system using Vav1-Cre (Stk4-/-Stk3-/-) resulted in a lethal bone marrow failure (median survival: 7 weeks) associated with myelodysplastic features and frequent extramedullary hematopoiesis in the spleen. A single copy of Stk4 rescued the lethality due to bone marrow failure, however sub-haploinsufficient mice displayed thrombocytopenia with a trend towards mild anemia; phenotypes that closely resemble those observed in MDS patients with isolated del(20q). Both a reduced number of mature megakaryocytes and the presence of dysplastic megakaryocytes were apparent in bone marrow sections. Inducible Hippo kinase inactivation in adult mice using the Mx1-Cre system similarly recapitulated several phenotypic features of both MDS and MPN. In competitive bone marrow transplant assays we found that Stk4-/-Stk3-/- hematopoietic stem cells (HSC) completely lacked engraftment potential and failed to reconstitute normal hematopoiesis, revealing a potential role for Hippo kinase function in HSC homing and retention in the bone marrow. Heterozygous HSCs maintained relatively normal steady-state hematopoiesis in peripheral blood and bone marrow for up to 48 weeks in primary and secondary transplantations, although upon aging these mice were prone to development of thrombocytopenia with increased mean platelet volume. Given the high frequency of del(20q) in MPN, especially PMF, we asked whether heterozygous Hippo kinase inactivation may cooperate with the common driver mutation JAK2-V617F to accelerate disease progression. Using an HSC-enriched retroviral transduction/transplantation model in C57BL/6 recipient mice, we monitored MPN progression for 36 weeks in heterozygous Stk4+/-Stk3+/-, or control (Vav1-Cre-), cells with or without expression of JAK2-V617F. While both JAK2-V617F groups initially displayed a similar degree of polycythemia relative to controls, we found heterozygous Hippo kinase inactivation to promote accelerated disease progression towards lethal bone marrow fibrosis during the course of observation. Recipients in this group showed significantly reduced overall survival, which was associated with higher grade fibrosis in bone marrow, elevated peripheral granulocyte counts, enhanced splenomegaly, and increased frequencies of hematopoietic stem and progenitor populations in the spleen. Together, these findings implicate aberrant Hippo kinase loss-of-function in the pathogenesis of del(20q)-associated hematologic malignancies, and shed new light on the molecular events that contribute to adverse MPN progression. Disclosures Bejar: Genoptix: Consultancy; Modus Outcomes: Consultancy; Celgene: Consultancy, Honoraria; Takeda: Research Funding; Astex/Otsuka: Consultancy, Honoraria; AbbVie/Genentech: Consultancy, Honoraria; Foundation Medicine: Consultancy. Guan:Vivace: Equity Ownership.

Importance Copy number alterations in programmed cell death ligand 1 ( PDL1 or CD274 ), programmed cell death 1 ligand 2 ( PDCD1LG2 or PDL2 ), and Janus kinase 2 ( JAK2 ) genes (chromosome 9p24.1) characterize Hodgkin lymphoma, resulting in high response rates to programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade. The prevalence and utility of PDL1 amplification as a response biomarker to PD-1/PD-L1 blockade are unknown in other tumors. Objectives To examine the prevalence of PDL1 amplification and its utility as a response biomarker to PD-1/PD-L1 blockade in solid tumors. Design, Setting, and Participants This retrospective study (October 1, 2012, to October 1, 2017) used a deidentified tumor database from a commercial company and annotated clinical records from a subset of patients treated at a university tertiary referral center. The study analyzed 118 187 tumors from the deidentified database, including a clinically annotated subgroup of 2039 malignant tumors. Interventions Comprehensive genomic profiling was performed on all samples to determine PDL1 amplification, microsatellite instability, and tumor mutational burden (TMB). A subset of patients was treated with PD-1/PD-L1 blockade. Main Outcomes and Measures The prevalence of PDL1 amplification was determined among 118 187 patient samples that underwent next-generation sequencing. Solid tumors treated with checkpoint blockade were evaluated for response and progression-free survival (PFS). Results Of the 118 187 deidentified tumor samples, PDL1 amplifications were identified in 843 (0.7%), including more than 100 types of solid tumors. Most PDL1 -amplified tumors (84.8%) had a low to intermediate TMB. PDL1 amplification did not always correlate with high-positive PD-L1 expression by immunohistochemical analysis. Six of 9 patients (66.7%) from 1 center with PDL1 -amplified solid tumors had objective responses after checkpoint blockade administration. The median PFS among all treated patients was 15.2 months. Responders included 1 patient with glioblastoma (PFS, ≥5.2 months), 2 patients with head and neck squamous cell cancer (PFS, ≥9 and 15.2 months), 2 patients with metastatic basal cell cancer (PFS, 3.8 and ≥24.1 months), and 1 patient with urothelial cancer (PFS, ≥17.8 months). Conclusions and Relevance The results of this study suggest that PDL1 amplification occurs in a small subset of malignant tumors. Additional large-scale, prospective studies of PDL1 -amplified cancers are warranted to confirm the responses to checkpoint blockade described herein, even in the absence of microsatellite instability, high PD-L1 expression, and a high TMB.

Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis characterized by xanthogranulomatous infiltration of foamy histiocytes frequently involving bone and other organ systems. We herein report a unique case of ECD discovered incidentally in an explanted liver in a 65-year-old male with end-stage liver disease secondary to hepatitis C cirrhosis. Histological examination and immunohistochemical studies in the explanted liver revealed prominent foamy histiocytes that were CD68 positive, but CD1a and S100 negative. Mutational hotspot analysis of the explanted liver using a panel of 47 most common cancer-related genes performed by next generation sequencing (NGS) revealed likely somatic mutations in the PDGFRA, PTEN, and HNF1A genes, but no BRAF codon 600 mutations were detected. The bone marrow showed similar findings as in the liver. Whole body PET and bone scans demonstrated increased heterogeneous uptake in bilateral humeral and femoral diaphysis, most compatible with ECD. To our knowledge, this is the first case report of ECD that involves mainly bone marrow and liver with novel genomic alterations. Our case highlights the diversity and complexity of this disease entity and the importance of multi-modality approach integrating clinical and radiologic features with histopathologic and molecular/genomic findings.

Feng Gao,2 Peng Jing,2 Jian Liu,2 Yuanfei Lu,1 Peicheng Zhang,2 Wei Han,1 Guoliang Liu,1 Ning Ru,2 Guanghui Cui,2 Chenglin Sun,1 Yebing Che,1 Huaming Zhang,1 Qnglong Hu,3 Huan-you Wang,4 Yingli Wu,2 Changjiang Guan,2 Qiang Fu,1 Zhenlu Ma,2 Baofa Yu1–3 1Jinan Baofa Cancer Hospital, Jinan, People's Republic of China; 2TaiMei Baofa Cancer Hospital, Dongping, People's Republic of China; 3Beijing Baofa Cancer Hospital, Beijing, People's Republic of China; 4Department of Pathology, UCSD School of Medicine, La Jolla, CA, USAPurpose: To compare the therapeutic effects of ultra-minimum incision personalized intratumoral chemoimmunotherapy (UMIPIC) with intratumoral chemotherapy (ITCT) in the treatment of advanced hepatocellular carcinomas and to analyze the effect of hapten as an immune booster.Materials and methods: Patients with advanced hepatocellular carcinomas were treated with UMIPIC or ITCT with the same therapeutic procedure; the UMIPIC method had a proprietary regimen including an oxidant, a cytotoxic drug, and hapten, while ITCT delivered the same drug excluding hapten. Of 339 patients in total, 119 of the UMIPIC patients (n=214) had response data and 214 had survival data, and of the ITCT patients (n=125), 61 had response data and 125 had survival data. Tumor response was assessed with a computed tomography scan 6–8 weeks after the initial treatment; the survival rate was evaluated by follow-up visits. Tumor size was classified as small (10 cm); tumor sizes with liver function categorized using Child–Pugh class (A and B) were analyzed by correlation with overall survival.Results: The response rates (complete response + partial response + stable disease) were 78.68% and 81.52% in the UMIPIC and ITCT groups, respectively, with no statistically significant difference; however, the median overall survival was 7 months for UMIPIC (test) and 4 months for ITCT (control), respectively (P

Double minute chromosomes (DMs), although relatively frequently encountered in solid tumors, are rare in hematologic neoplasms such as acute myeloid leukemia (AML), and even rarer in lymphoid neoplasms. t(3;3)(q26.2;q21) is a very rare genetic alteration observed in myeloid neoplasm. Herein we report an interesting and unique case of concomitant C-MYC DMs and t(14;18)-containing large B-cell lymphoma, which was successfully treated with R-hyper-CVAD; unfortunately, the patient has developed a therapy-related AML (t-AML) 2 years since the start of his lymphoma treatment. His t-AML contains both t(3;3)(q26.2;q21) and monosomy 7, and the patient died of AML 10 months after the initial diagnosis of t-AML despite clinical remission. To the best of our knowledge, this is the first reported case of C-MYC DM-containing de novo large B-cell lymphoma, which was successfully treated with complete remission, but unfortunately died of t-AML harboring t(3;3)(q21;q26).

Baofa Yu,1–3 Yuanfei Lu,1 Feng Gao,2 Peng Jing,2 Han Wei,1 Peicheng Zhang,2 Guoliang Liu,1 Ning Ru,2 Guanghui Cui,2 Xinhai Xu,1 Chenglin Sun,1 Changjiang Guan,2 Yebing Che,1 Yingli Wu,2 Zhenlu Ma,2 Qiang Fu,1 Jian Liu,2 Huan-You Wang4 1Jinan Baofa Cancer Hospital, Jinan, 2TaiMei Baofa Cancer Hospital, Dongping, 3Beijing Baofa Cancer Hospital, Beijing, People’s Republic of China; 4Department of Pathology, University of California, San Diego, CA, USAAim: The objective of the study reported here was to evaluate the therapeutic effects of hapten-enhanced chemoimmunotherapy in the treatment of advanced lung cancer by ultra-minimum incision personalized intratumoral chemoimmunotherapy (UMIPIC) and to analyze the effect of this immune booster.Materials and methods: A total of 97 patients with advanced lung cancer were treated with UMIPIC or intratumoral chemotherapy (ITCT). UMIPIC was delivered intratumorally in combination with a proprietary therapeutic regimen composed of three components – an oxidant, a cytotoxic drug, and hapten. ITCT applied using the same procedures and regimen, only without hapten. All data from the two groups were reviewed and analyzed. A total of 55 patients were treated with UMIPIC and 42 with ITCT. Patient responses were assessed with computed tomography scan 4–6 weeks after treatment, and all of the patients were followed until their deaths.Results: Median overall survival was 11.23 months in the UMIPIC (test) group and 5.62 months in the ITCT (control) group (P

Histiocytic sarcoma (HS) is a rare, aggressive malignancy. Lesions previously called HS were typically non-Hodgkin lymphomas, not HS. As such, chemotherapy directed at lymphoid neoplasms was frequently successful, but it is unclear if these regimens are ideal for HS. We present a 33-year-old African gentleman who underwent sequential renal transplants for glomerulonephritis. He subsequently developed HS of the upper airway and multiple cutaneous sites. The patient received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) followed by salvage ifosfamide, carboplatin, and etoposide (ICE) but had continuous progression of cutaneous involvement. Cladribine, high-dose cytarabine, G-CSF, and mitoxantrone (CLAG-M) yielded a partial response with near resolution of disease. Ultimately, the patient achieved a complete remission after myeloablative allogeneic hematopoietic stem cell transplant. HS occurring after solid organ transplant raises the possibility of HS as a potential posttransplant malignancy. The use of CLAG-M has not been reported in HS. In this case, histiocyte-directed chemotherapy with CLAG-M was superior to lymphoma-directed regimens.

[Figure][1] The patient is a 65-year-old man with HIV/AIDS. In February 2016, he presented to an outside hospital with ascites (panel A; hematoxylin and eosin stain, original magnification ×400) and a diagnosis of MYC -rearranged (panel B) CD5–dimly positive (panel C) “aggressive large

Primary cutaneous γδ T-cell lymphoma and hemophagocytic syndrome (HPS) is a very rare disease process with only 41 cases of this type of lymphoma published to date. We report the case of a 56-year-old woman who developed high-grade fevers and multiple nonhealing bilateral lower extremity ulcers associated with a recent diagnosis of Ackerman syndrome. Multiple lesion biopsies yielded a differential diagnosis including sarcoidosis and lupus panniculitis. Each biopsy site developed into a poorly healing wound. After extensive rheumatologic and dermatologic workup, failed courses of hyperbaric oxygen and corticosteroids, and the development of worsening fevers, the diagnosis of γδ T-cell lymphoma was made. The objective of this article was to illustrate a very rare case of a rapidly progressing cutaneous lymphoma while stressing the importance of a surgical approach to nonhealing wounds and biopsy in chronic wounds.An aggressive multidisciplinary approach including infectious disease, hematology/oncology, nephrology, plastic surgery, and interventional pulmonology was used. Medical approaches included several courses of corticosteroids and antineoplastics. Our surgical approach included numerous excision and debridements of her nonhealing ulcers with removal of necrotic tissue. It also included placement of cadaveric epidermal graft, and bovine tendon collagen cross-linked with glycosaminoglycans with a silicone matrix bilayer (Integra, Plainsboro, NJ) combined with multiple local myocutaneous advancement flaps. This approach demonstrated clinical improvement in wound healing. Pathological examination of several lesions included immunohistochemistry staining, flow cytometry, and molecular studies.The diagnosis of primary cutaneous γδ T-cell lymphoma was made based on a pathology specimen. Subsequent imaging showed numerous pulmonary nodules later determined to be pulmonary Aspergillosis. Additionally, she developed a constellation of clinical and laboratory features defined as the HPS. Despite medical therapy and improved wound healing, she died to seizures that left her comatose, thought to be secondary to central nervous system advancement of her HPS. The patient eventually died after care was withdrawn.Cutaneous forms of lymphoma must be considered in the differential diagnosis of atypical cutaneous lesions or nonhealing wounds. There should be no delay in performing a skin biopsy to obtain a tissue diagnosis. A surgical approach to wounds clearly demonstrates improved wound healing.

Balanced translocation between chromosomes 3q26 and 8q24 is a very rare event. Here we report six patients with t(3;8)(q26;q24) either as a sole or as a part of genetic abnormalities. Five of the six patients were men with ages ranging from 41 to 84 years old. One patient had a long history of granulocyte colony stimulating factor (G-CSF) treatment. Three of the patients were initially diagnosed with acute myeloid leukemia, two with myelodysplastic syndrome and one with chronic myelogenous leukemia with blast crisis. The peripheral blood in all patients showed severe to moderate anemia; one had absolute neutropenia, one with neutrophilia; four had thrombocytopenia, two with thrombocytosis. The bone marrows from all patients showed dysmegakaryopoiesis with additional erythroid (three patients) and granulocytic (two patients) dysplasia. Cytogenetics revealed t(3;8)(q26;q24) as the sole abnormality in three patients. The majority of patients (4/6) had a poor clinical course, with an average survival of 10 months.

As a distinct type of aggressive mature large B-cell lymphoma, plasmablastic lymphoma (PBL) poses diagnostic and treatment challenges. PBL is distinguished from other B-cell lymphomas by the presence of plasmacytic differentiation markers such as CD38, CD138, and MUM1. Clinically, PBLs from oral and extra-oral sites are rapidly progressive tumors with frequent relapse after treatment with standard diffuse large B-cell lymphoma regimens. Here, we report a near-complete response of one patient with relapsed PBL following treatment with a non-cytotoxic regimen containing bortezomib, rituximab, and dexamethasone.

Objective: To test the hypothesis that reperfusion of the canine lung after 1 week of vascular occlusion results in acute injury of the reperfused lung with concurrent impairment in gas exchange. Methodology: In 11 conditioned dogs, the left pulmonary artery was completely occluded by a vascular clip placed at thoracotomy. One week later, at repeat thoracotomy, the clip was removed in six animals (reperfused group) but left in place in five (sham group). Bronchoalveolar lavage fluid (BAL) components, gas exchange, haemodynamics and histological alterations were examined. Results: During occlusion, the mean pulmonary artery pressure and pulmonary vascular resistance increased significantly, and after 6 days there was a significant increase in ventilation to high ventilation perfusion ratio (V/Q) areas. With reperfusion, the previously occluded lung demonstrated, in comparison to the contralateral lung, a significant increase in BAL cellularity and neutrophil fraction, gross and histological evidence of oedema, and impaired surfactant activity. Shunt fraction, measured by the inert gas technique, also increased only after reperfusion, although mild hypoxaemia occurred in both groups. Endothelial abnormalities and perivascular oedema were noted in both groups, but were more marked in the reperfused lungs. Conclusion: Reperfusion of the canine lung after 1 week of complete occlusion resulted in evidence of mild acute lung injury. The aetiology of this injury was multifactorial.

[Figure][1] A 79-year-old woman presented with new-onset weight loss, bilateral axillary lymphadenopathy (LAD), and a chest wall mass. A complete blood count showed a leukocytosis of 87 600/μL with 99% lymphocytes. A review of the peripheral blood smear and flow cytometry (data not shown

Primary gastrointestinal (GI) T-cell lymphoma is an infrequent and aggressive disease. However, rare indolent clonal T-cell proliferations in the GI tract have been described. We report 10 cases of GI involvement by an indolent T-cell lymphoproliferative disease, including 6 men and 4 women with a median age of 48 years (range, 15-77 years). Presenting symptoms included abdominal pain, diarrhea, vomiting, food intolerance, and dyspepsia. The lesions involved oral cavity, esophagus, stomach, small intestine, and colon. The infiltrates were dense, but nondestructive, and composed of small, mature-appearing lymphoid cells. Eight cases were CD4(-)/CD8(+), 1 was CD4(+)/CD8(-), and another was CD4(-)/CD8(-). T-cell receptor-gamma chain gene rearrangement identified a clonal population in all 10 cases. There was no evidence of STAT3 SH2 domain mutation or activation. Six patients received chemotherapy because of an initial diagnosis of peripheral T-cell lymphoma, with little or no response, whereas the other 4 were followed without therapy. After a median follow-up of 38 months (range, 9-175 months), 9 patients were alive with persistent disease and 1 was free of disease. We propose the name "indolent T-LPD of the GI tract" for these lesions that can easily be mistaken for intestinal peripheral T-cell lymphoma, and lead to aggressive therapy.

Background: Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is a rare peripheral T-cell lymphoma, accounting for approximately 3% of adult non-Hodgkin lymphomas (NHL). In this report we describe an unusual case of an ALK(+) ALCL, which presented as an aggressive mass involving upper nasal cavity and anterior skull base. The pathogenesis, histopathology with radiologic correlations, and management of this case are reviewed. Case Description: A 28-year-old Asian female presented with a 3-month history of nasal congestion culminating in epistaxis. Physical examination was notable for a tissue mass obstructing nasal cavity and the sphenoid sinus. Computed tomography (CT) and magnetic resonance (MR) imaging revealed a lesion primarily involving the upper nasal cavity extending intracranially through the cribriform plates into the anterior cranial fossa. Histologic and immunohistochemical analysis of the specimen obtained through a transnasal biopsy revealed an ALK(+) ALCL. The patient underwent two cycles of chemotherapy and focal radiation therapy, achieving minimal residual disease. The patient remained neurologically unchanged with stable minimal residual disease at the 1-year follow-up. Conclusions: To the best of our knowledge, this is the first case of an ALK(+) ALCL that presented as an aggressive upper nasal cavity and anterior skull base lesion. This case report highlights the importance of multi-modality approaches including preoperative imaging and tissue biopsy for definitive diagnosis.

[Figure][1] A 91-year-old woman was found to have bilateral cervical and right supraclavicular lymphadenopathy by computed tomography scan following an accident. There was no M-paraprotein in serum and there were no lytic bone lesions. Fine needle aspiration of the right cervical lymph node

Primary effusion lymphoma (PEL) is a rare form of aggressive B-cell lymphoma in HIV patients, which typically presents with lymphomatous effusions in the body cavities without forming mass lesions. PEL is associated with Kaposi sarcoma-associated herpesvirus (KSHV) (also called human herpesvirus-8) with distinct clinical and pathologic features. Rare cases of KSHV-associated large B-cell lymphoma (KSHV-LBL) have been observed in the lymph nodes or extranodal sites without lymphomatous effusions during the course of disease. KSHV-LBL is generally similar to classic PEL on the basis of the clinical presentation (HIV(+) male), morphology (immunoblastic, plasmablastic, or anaplastic), immunophenotype (CD45(+), CD20(-), CD79a(-), CD30(+), CD138(+), and EMA(+)), presence of Epstein-Barr virus infection, and clonal immunoglobulin gene rearrangements. However, it is not clear whether KSHV-LBL is a distinct entity or represents part of the spectrum of classic PEL; in particular, there is no consensus diagnostic term for KSHV-LBL. In this study, we investigated the clinicopathologic features of 9 cases of KSHV-LBL from our files. An additional 43 such cases and 84 cases of classic PEL from the English literature were reviewed and compared with each other. In contrast to the classic PEL, KSHV-LBL had a very significant lower expression of CD45 (74% vs. 94%, P=0.004) but significant higher expression of CD20 (17% vs. 5%, P=0.04) and CD138 (70% vs. 38%, P=0.05). KSHV-LBL also had slightly higher positivity of CD79a (23% vs. 5%, P=0.13) and immunoglobulin light chain expression, although the difference was not statistically significant [κ chain (12% vs. 0%) and λ chain (31% vs. 21%)]. The expressions of EMA and CD30 were slightly lower in KSHV-LBL compared with those observed in PEL (57% vs. 75% and 63% vs. 76%, respectively). Interestingly, 29% (10/34) of cases of KSHV-LBL revealed aberrant CD3 expression, which may mislead to a diagnosis of T-cell lymphoma, particularly anaplastic large cell lymphoma in combination with the anaplastic morphology and expression of CD30 and EMA. Although KSHV-LBL shows different clinical presentations and some variations in immunophenotype from classic PEL, it is still uncertain, on the basis of our findings, whether it is justifiable to separate them as 2 distinct entities. Nevertheless, we feel it is necessary to have a consensus diagnostic term, and we recommend a tentative one as "KSHV-associated large B-cell lymphoma (KSHV-LBL)" to replace many different names previously used.