EBV-positive T/NK-associated lymphoproliferative disorders of childhood: A complete autopsy report.

INTRODUCTION: Epstein-Barr Virus (EBV)-associated systemic T-cell lymphoproliferative disorder of childhood is a rare but severe manifestation of chronic EBV infection. Despite several case reports characterizing this rare hematological neoplasm, the literature describes extensive heterogeneity in the presentation of this disease. CASE PRESENTATION: Here we present a complete autopsy of a 16-year-old girl who ultimately succumbed to EBV-associated systemic T-cell lymphoproliferative disorder of childhood. Her clinical presentation demonstrated a non-specific pharyngitis with positive mono spot test, evolving into fulminant multi-organ failure, disseminated intravascular coagulopathy, sepsis, and ultimately death. CONCLUSIONS: Post-mortem findings included extensive hemorrhage, and infiltration of the liver, spleen, lymph nodes and bone marrow with neoplastic T-cells. There was extensive hemophagocytic lymphohistiocytosis (HLH) within these organs, suggesting overlap between the EBV-associated systemic T-cell lymphoproliferative disorder of childhood and EBV-associated HLH. We hope these findings provide a more comprehensive overview of several possible manifestations of EBV-associated systemic T-cell lymphoproliferative disorder of childhood.

Iatrogenic immunodeficiency-associated lymphoproliferative disorders in transplant and nontransplant settings.

Iatrogenic immunodeficiency-associated lymphoproliferative disorders comprise a group of lymphoid neoplasms that are associated with an immunosuppressed state, either in the posttransplant period, or during the treatment of various autoimmune and rheumatologic disorders by immunomodulatory medications. Their morphologies vary widely but are generally classified according to the lymphomas that they most closely resemble. This group is strongly associated with infections by the Epstein-Barr virus as a result of impaired immune function in the immunosuppressed state. Although further classification may become necessary in the coming years, they are distinguished from lymphomas in immunocompetent hosts because reduction or cessation of immunosuppressive or immunomodulatory therapy can result in complete clinical remission.

Overdiagnosis of high-grade dysplasia in Barrett's esophagus: a multicenter, international study.

Numerous histological mimics of high-grade dysplasia in Barrett's esophagus predispose to overdiagnosis and potential serious mismanagement, including unnecessary esophagectomy. This study investigates the prevalence and sources of this problem. Biopsies from 485 patients diagnosed with Barrett's high-grade dysplasia were screened for a multi-institutional, international Barrett's endoscopic ablation trial. Screening included review of the original diagnostic slides and an additional protocol endoscopy with an extensive biopsy sampling. Observer variability by the study pathologists was assessed through two blinded diagnostic rounds on 437 biopsies from 26 random study endoscopies. Study diagnostic reassessments revealed significantly lower rates of high-grade dysplasia. Only 248 patients (51%) were confirmed to have high-grade dysplasia. The remaining patients had inflamed gastric cardia without Barrett's (n=18; 7%), Barrett's without dysplasia (n=35; 15%), indefinite change (n=61; 26%), low-grade dysplasia (n=79; 33%), adenocarcinoma (n=43; 18%), and other (n=1; <1%), yielding an alarming total of 194 or 40% of patients who were overdiagnosed with Barrett's high-grade dysplasia. Study pathologists achieved a high-level agreement (90% three-way inter-observer agreement per biopsy, Kappa value 0.77) for high-grade dysplasia. Confounding factors promoting overdiagnosis included Barrett's inflammatory atypia (n=182), atypia limited to the basal metaplastic glands (n=147), imprecise criteria for low grade neoplasia (n=102), tangential sectioning artifact (n=59), and reactive gastric cardiac mucosa (n=38). A total of 194 patients (40%) were overdiagnosed with Barrett's high-grade dysplasia, as affirmed by the extensive screening process and high-level study pathologist agreement. The multiple diagnostic pitfalls uncovered should help raise pathologists' awareness of this problem and improve diagnostic accuracy.

Optimized immunohistochemical panel to differentiate myeloid sarcoma from blastic plasmacytoid dendritic cell neoplasm.

Myeloid sarcoma (MS) and blastic plasmacytoid dendritic cell neoplasm (BPDCN) can be difficult to distinguish morphologically, even with the use of extensive immunohistochemical studies. Three new research markers, myxovirus A (MxA), CLA/CD162, and CD303/BDCA-2, have been reported to be positive in BPDCN, but their clinical utility has never been tested. We compared these markers to other antibodies that have been used traditionally to distinguish MS from BPDCN to assess the utility of these newer antibodies in differential diagnosis. Formalin-fixed, paraffin-embedded tissue sections of 23 MS and 17 BPDCN cases were assessed using immunohistochemical analysis for CD4, CD14, CD33, CD43, CD56, CD68, CD123, CD163, myeloperoxidase, lysozyme, terminal deoxynucleotidyl transferase (TdT), T-cell leukemia 1 (TCL-1), MxA, cutaneous lymphocyte-associated antigen (CLA)/CD162, and blood dendritic cell antigen 2 (BDCA2)/CD303. We identified antibodies with a high predictive value of ≥ 90% and used these markers to develop an approach to classification using specific staining criteria. Diagnostic classification criteria were based on staining patterns of one or more of the seven markers. BPDCN was associated with positive staining for CD56, TdT, or TCL1, or negative staining for lysozyme. MS was associated with positive staining for lysozyme or myeloperoxidase, or negative staining for CD56, CD123, myxovirus, or TCL1. The immunohistochemical staining patterns observed using a panel that includes MPO, CD56, CD123, TCL1, TdT, and MxA, are predictive of MS or BPDCN. In this study, neither CD162 nor CD303 had good predictive value in distinguishing MS from BPDCN.

Aberrant expression of multiple T antigens: CD4, CD5, and CD8 on diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Aberrant expression of T antigens (exclusive of CD5) in DLBCL has been described in the literature; however, coexpression of 2 or more T antigens is rare. We report a case with a well-established diagnosis of DLBCL, coexpressing 3 T-cell antigens, CD4, CD5, and CD8. Although the clinical significance of T antigen coexpression in DLBCL is unclear, it is important to be aware of such phenotypic plasticity to ensure accurate diagnoses are made. The expression of multiple T-cell antigens may introduce diagnostic confusion and make subclassification of a lymphoma using World Health Organization criteria difficult.

A retrospective review of UroVysion fish interpretations over 8.6 years: a major shift in the patient test population.

UroVysion FISH detects chromosomal aberrations associated with urothelial carcinoma. In our laboratory, UroVysion FISH was initially evaluated manually with a change to image-aided interpretation using the BioView Duet imaging system. This retrospective study examined diagnostic findings over an 8.6 year period, with 1,869 manual interpretations over 4.8 years and 3,936 image-aided interpretations over 3.8 years. Although the initial goal was to evaluate possible impacts of the imaging system on diagnostic interpretations, the most important finding was that the demographics of the test population changed significantly. Female specimens increased incrementally from an average of 29% compared to 43% of the samples during periods of manual interpretation versus image-aided interpretation, respectively. The shift may reflect a gradual increase in the percentage of low-risk hematuria patients being evaluated for initial diagnosis of bladder cancer, rather than bladder cancer recurrence. Interpretation rates, evaluated separately for males and females, changed significantly over the test period. Male interpretation results were negative (75.1 vs. 67%), positive (18.6 vs. 14.6%), unsatisfactory (5.0 vs. 16.9%), and equivocal (1.4 vs. 1.5%) during periods of manual versus image-aided interpretation, respectively (Fisher Exact Test P-value = <0.0001). For females, results were negative (86.1 vs. 79.3%), positive (9.2 vs. 11.1%), unsatisfactory (2.8 vs. 8.9%), and equivocal (1.8 vs. 0.7%) over the same periods (Fisher Exact Test P-value = <0.0001). Logistic regression analysis identified the change in test population as the variable with the greatest impact on observed interpretation rate changes.

Novel molecular aberrations and pathologic findings in a tubulocystic variant of renal cell carcinoma.

Tubulocystic renal cell carcinoma (TRCC) is an indolent type of renal cell carcinoma with a good prognosis based on the limited number of published cases. Herein, we describe the unusual clinical, pathologic and molecular findings in a case of TRCC. Our patient with TRCC had two local recurrences and a brain metastasis following radical nephrectomy. Unusual histologic findings included focal solid growth pattern and cytologic atypia. A genome-wide molecular inversion probe assay identified copy number (CN) loss in three chromosome regions and one region with copy-neutral loss of heterozygosity (copy-neutral LOH). Copy number variations (CNVs) were observed (chromosomes 4p16.1 and 17q21.31-q21.32) in both the tumor and the normal tissue, and most likely represents benign variations. The loss of entire chromosomes 9, 18 and 15 and copy-neutral LOH involving 6p22.1 was observed only in the tumor. The presence of these clinical, pathologic and molecular findings could be related to an increased risk for tumor recurrence and poor prognosis. The novel molecular findings described in TRCC might represent new targets for novel therapies.

Telangiectatic osteosarcoma.

Osteosarcoma is one of the most common primary malignant bone tumors in children and adolescents. Telangiectatic osteosarcoma is an unusual variant of osteosarcoma, forming 3% to 10% of all osteosarcomas. Radiographically, these tumors appear as purely lytic destructive lesions located in the metaphyses of long bones. The location and x-ray appearance of telangiectatic osteosarcomas are reminiscent of an aneurysmal bone cyst and can test the acumen of a diagnostic radiologist. Distinguishing between the two entities microscopically can also be quite challenging. Telangiectatic osteosarcoma shows dilated blood-filled spaces lined or traversed by septa containing atypical stromal cells, with or without production of a lacelike osteoid matrix. This review highlights the diagnostic features of telangiectatic osteosarcoma and discusses differential diagnostic considerations, treatment options, and prognostic implications.

Core-binding factor acute myeloid leukemia.

Core-binding factor acute myeloid leukemia (AML) is cytogenetically defined by the presence of t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), commonly abbreviated as t(8;21) and inv(16), respectively. In both subtypes, the cytogenetic rearrangements disrupt genes that encode subunits of core-binding factor, a transcription factor that functions as an essential regulator of normal hematopoiesis. The rearrangements t(8;21) and inv(16) involve the RUNX1/RUNX1T1 ( AML1-ETO ) and CBFB/MYH11 genes, respectively. These 2 subtypes are categorized as AML with recurrent genetic abnormalities, and hence the cytogenetic fusion transcripts are considered diagnostic of acute leukemia even when the marrow blast count is less than 20%. The t(8;21) and inv(16) subtypes of AML have been usually grouped and reported together in clinical studies; however, recent studies have demonstrated genetic, clinical, and prognostic differences, supporting the notion that they represent 2 distinct biologic and clinical entities. This review summarizes the spectrum of this subset of AMLs, with particular emphasis on molecular genetics and pathologic findings.

Antiphospholipid antibody syndrome.

Antiphospholipid antibodies are directed against phospholipid-protein complexes and include lupus anticoagulant, anticardiolipin antibodies, and anti-beta-2 glycoprotein I antibodies. Antiphospholipid antibody syndrome is a common cause of acquired thrombophilia and is characterized by venous or arterial thromboembolism or pregnancy morbidity and the presence of antiphospholipid antibodies. Antibodies should be demonstrable on at least 2 occasions separated by 12 weeks. Heterogeneity of the autoantibodies and absence of gold standard assays makes interpretation of laboratory results a challenge for both laboratorians and clinicians. This review discusses the key laboratory and clinical aspects of antiphospholipid antibody syndrome. Particular focus is given to lupus anticoagulant detection, in view of recently updated laboratory guidelines.

Diffuse large B-cell lymphoma with aberrant expression of the T-cell antigens CD2 and CD7.

Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma. Although, aberrant expression of a single T-cell-associated antigen (exclusive of CD5) on diffuse large B-cell lymphoma has occasionally been described in the literature, cases that show coexpression of ≥2 T-cell antigens on a well-documented case of diffuse large B-cell lymphoma are extremely rare. Here, we describe a well-characterized case of diffuse large B-cell lymphoma that showed aberrant coexpression of 2 T-cell-associated antigens, CD2 and CD7. Recognition of these types of cases is important to help ensure accurate diagnoses are made.

Uterine mesenchymal tumors.

Uterine mesenchymal tumors are a heterogeneous group of neoplasms that can frequently be diagnostically challenging. Differentiation between the benign and malignant counterparts of mesenchymal tumors is significant due to differences in clinical outcome, and the role of the surgical pathologist in making this distinction (especially in the difficult cases) cannot be underestimated. Although immunohistochemical stains are supportive toward establishing a final diagnosis, the morphologic features trump all the other ancillary techniques for this group of neoplasms. This review therefore emphasizes the key morphologic features required to diagnose and distinguish uterine mesenchymal tumors from their mimics, with a brief description of the relevant immunohistochemical features.

Prevalence of heparin in samples submitted for lupus anticoagulant testing.

INTRODUCTION: Lupus anticoagulant (LA) testing can be affected by the presence of anticoagulant medications such as heparin, and current guidelines recommend caution when performing and interpreting LA testing for patients who are receiving anticoagulation treatment. We searched our reference laboratory database to determine the prevalence of heparin in samples submitted for LA testing. METHODS: We reviewed 18,676 LA reflexive testing panels. Heparin was identified by partial thromboplastin time (before and after heparin neutralization), thrombin time, and reptilase time results. Samples containing heparin were subclassified (not significant, significant) according to the degree of thrombin time prolongation. RESULTS: Of the panels, 1909 panels (10%) were LA positive. We found that 2011 samples (11%) contained some heparin and that 616 samples contained a significant amount of heparin (3% of all samples and 31% of samples containing heparin). LA-positive results were obtained for 80 (13%) of these samples, which represented 4% of the samples containing heparin and 0.4% of all samples. CONCLUSION: LA-testing guidelines recommend that samples not contain anticoagulant medications. Despite these recommendations, our data show that a significant proportion (11%) of these samples contain heparin. We conclude that LA-testing algorithms should use methods to identify and neutralize heparin and that laboratories should provide education regarding appropriate sample collection for LA testing.