B-cells behaving badly I: A better basis to behold belligerence in small b-cell lymphomas

ABSTRACTS

PROFICIENCY TESTING IN BONE MARROW MORPHOLOGY John Sioufi, Katherine Marsden RCPAQAP Haematology, St Leonards, NSW, Australia Aim: The RCPAQAP blood film morphology module originated in 1963 unable to offer a bone marrow (BM) morphology module as it was not possible to obtain the number of slides required for a survey. Virtual microscopy overcomes this problem and the aim was to determine the feasibility of a BM morphology survey using online virtual microscope scans. Method: A pilot survey was sent to all laboratories enrolled in the RCPAQAP Morphology module. Virtual microscopy scans of the blood film, bone marrow aspirate and trephine from an essential thrombocythaemia (ET) patient were used. Participation involved providing a bone marrow differential count, a diagnosis and recommended additional investigations. Results: The uptake was low despite reminders and extensions of the closing date. Forty participants completed the differential count; 30–39 answered survey questions and/or provided other feedback. The diagnoses made were ET 31/39 participants (80%), other myeloproliferative neoplasms 5/39 (13%), other diagnoses 3 (8%). Conclusion: The reasons for the low response rate are not known but we conclude that many laboratories could now manage an online virtual bone marrow morphology survey. As a result the RCPAQAP will introduce a bone marrow morphology module in 2016 but ensure that DVDs are available if preferred. THROMBOPHILIA INVESTIGATION – NOT FOR EVERYONE Sam Schulman Department of Medicine, McMaster University, Hamilton, ON, Canada ‘All truths are easy to understand once they are discovered; the point is to discover them’ (Galileo Galilei). Many physicians believe that a thrombophilia work-up will provide the explanation for a thrombotic event and thousands of dollars have been spent on these investigations. For arterial thromboembolic events a thrombophlia investigation is rarely positive and it will never lead to any beneficial change in management of the patients. In venous thromboembolism it can demonstrate abnormalities in up to 50% of the cases, depending on how they are selected. False positive results are common if the blood sampling is performed when an anticoagulant drug is present. The most affected tests are lupus anticoagulant, protein C, protein S and antithrombin. The acute phase reaction as well as liver dysfunction secondary to large pulmonary embolism with right heart strain can also distort the results. A negative investigation does not mean that the patient has no thrombophilic condition, since some abnormalities surely remain to be discovered. Before embarking on a thrombophilia work-up some questions need to be answered: (1) will the result change the management—probably not if the condition requires indefinite anticoagulation—and (2) if not, is it for information and preventive measures for family members, and in that case, are they interested? The evidence that such information will change prognosis is very weak.

S37

NEW ANTICOAGULANTS, WHY ARE THEY DIFFERENT Sam Schulman Department of Medicine, McMaster University, Hamilton, ON, Canada The non-vitamin K antagonist oral anticoagulants (NOACs) have several characteristics that differ from vitamin K antagonists (VKAs). NOACs have quick onset and shorter half-life, which are mostly favourable features. However, for patients with poor adherence the short half-life poses a greater risk of lost efficacy, together with the absence of supervision required for the VKAs. The risk of bleeding is similar or lower with NOACs; most importantly, there is a reduction of the risk of intracranial haemorrhages, explained by the severe impairment of tissue factor pathway initiation of coagulation with VKAs but not with NOACs. On the other hand, NOACs are associated with more bleeding from the distal gastrointestinal canal due to the high concentration of active drug in the bowel. This is a result of the efflux transporter, P-glycoprotein. A similar mechanism may be responsible for the increased incidence of menorrhagia with some NOACs. The management of anticoagulants for surgery must take into account the different pharmacokinetic characteristics of the anticoagulants. Local protocols should be established to standardise peri-operative management in order to minimise the risk for thromboembolic and haemorrhagic complications. The NOACs have more or less dependence on renal function for elimination, which limits their use. Drug-drug interactions are substantially fewer for the NOACs. Rivaroxaban at treatment doses is dependent on concomitant food intake for optimal absorption B-CELLS BEHAVING BADLY I: A BETTER BASIS TO BEHOLD BELLIGERENCE IN SMALL B-CELL LYMPHOMAS Adam Bagg Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA Small B-cell lymphomas and leukaemias (SBCLs) are a clinically, morphologically, immunophenotypically and genetically heterogeneous group of neoplasms that include chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), lymphoplasmacytic lymphoma (LPL), marginal zone lymphoma (MZL) and hairy cell leukaemia (HCL). The pathogenesis of some of these lymphoid malignancies is characterised by distinct translocations, for example t(11;14) and t(14;18), respectively, in most cases of MCL and FL. By contrast, other entities are associated with a variety of non-specific and nondiagnostic but nevertheless recurrent and prognostically pertinent numeric abnormalities, such as del(17p), del(13q14), del(11q22) and +12 in CLL. Yet others like LPL and HCL lack specific cytogenetic aberrations. The recent surge in next generation sequencing technology has shed abundant light on the genetic landscape of SBCLs through characterisation of numerous driver mutations including BRAF (V600E) in HCL and MYD88 (L265P) in LPL, amongst others. These significant advances and panoply of available tests notwithstanding, it is important to appreciate that not all SBCLs need genetic testing for diagnosis, not all harbour their characteristic genetic features

S38

PATHOLOGY 2016 ABSTRACT SUPPLEMENT

and not all are diagnostically specific. This lecture will attempt to review the role of genetic studies in SBCLs, highlighting their advantages and limitations.

Pathology (2016), 48(S1)

and biopsies for vascular deposition of the same TCC/MAC (either involved organ or random skin biopsies). Reference 1. Nester C, Barbour T, de Cordoba SR, et al. Atypical aHUS: state of the art. Mol Immunol 2015; 67: 31–42.

B-CELLS BEHAVING BADLY II: A BETTER BASIS TO BEHOLD BELLIGERENCE IN AGGRESSIVE B-CELL LYMPHOMAS Adam Bagg Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA Aggressive B-cell lymphomas include diffuse large B-cell lymphoma (DLBCL), the most common type of lymphoma encountered in most countries. Despite the single term, DLBCLs are a rather diverse group of lymphomas that can be subclassified using a variety of different approaches, including anatomical site, morphology, immunophenotype, and a number of genetic strategies. Nascent molecular technologies have led to the discovery of many of the genetic events underlying the pathogenesis of this group of diseases. Whether by defining gene signatures that subclassify DLBCL into subgroups based upon cell-of-origin, through dysregulation of key cellular pathways, or specific mutations, we are approaching an era in which personalised diagnostics, prognostication and therapy are imminent. Attempts to develop surrogate immunohistochemical algorithms for some of these genetic phenomena have been variably successful. This lecture will focus on DLBCL and highlight one particular shade of so-called grey zone lymphoma and its relationship to double-hit lymphomas. An attempt will also be made to synthesise the rational use of genetic testing of lymphomas covered in both this and the preceding lecture on small B-cell neoplasms. TESTS FOR TTP/aHUS Theo de Malmanche Pathology North (Hunter) Immunology, Newcastle, NSW, Australia Thrombotic thrombocytopenic purpura (TTP) follows an excess of ultra large multimers of von Willebrand factor (vWF), which follows reduced serum ADAMTS13 activity. Microangiopathy which follows intoxication with Shiga toxins, e.g., some E. coli (STEC) are perhaps best labelled as STEC-HUS. ADAMTS13 activity and stool STEC toxin are specific assays for these diseases. Many STEC negative/ADAMTS13 replete cases are complement mediated. Organ damage will occur without affecting routine complement assays. Triggering events are minor and not specific for microangiopathy (e.g., rotavirus). Testing aims to demonstrate (1) the predisposing tendency to complementmediated microangiopathy (detected in ~30% of cases) or (2) complement activation (largely anecdotal and case studies). Abnormalities of regulators of complement activation (RCA) molecules have the highest yield, specifically, complement factors H and I (CFH, CFI), and membrane cofactor protein (MCP, CD46. Complement component 3 (C3), complement factor B, thrombomodulin have a lower yield. Complement activation can be demonstrated with serum levels of terminal complement complex (TCC, aka sMAC, or sC5b-9)

AN UPDATE ON TTP INCLUDING DATA FROM THE AUSTRALIAN TTP/TMA REGISTRY P. Blombery Peter MacCallum Cancer Centre and Monash University, Melbourne, Vic, Australia Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy (TMA) which is the result of a severe deficiency of ADAMTS13 activity. In the majority of cases, the ADAMTS13 deficiency is the result of auto-antibodies produced against ADAMTS13 which impair protein activity. With the recognition and characterisation of the pathological basis of acquired TTP has come rational therapies including more targeted and less toxic immunosuppression (e.g. rituximab), targeted agents against the vWF platelet interaction (caplacizumab) and recombinant ADAMTS13. The Australian TTP/TMA registry was established to collect data on Australian patients with all TMAs with the aim of creating a resource to help assess the patterns of diagnosis and management of this group of disorders in Australia. The registry is maintained by the Monash University Department of Epidemiology and Preventive Medicine (DEPM) under the auspices of the Transfusion Outcomes Research Collaboration, a partnership with the Australian Red Cross Blood Service (ARCBS), and began collecting data in 2009. Analysis of data from patients with TTP in the TTP/TMA registry has given insights into the current state of diagnosis and treatment of TTP in Australian patients and identified potential areas for practice improvement which will be shared in this presentation. aHUS IN CHILDREN: A SEVERE DISEASE WITH INCREASINGLY BETTER DIAGNOSTIC AND TREATMENT OPTIONS Stephen Alexander Children’s Hospital at Westmead, NSW, Australia Atypical haemolytic uraemic syndrome (aHUS) accounts for around 10% of children presenting with haemolytic uremic syndrome, a triad of thrombocytopenia, haemolytic anaemia and renal failure. As opposed to diarrhoeal causes usually associated with E. coli infection producing the toxin STEC, aHUS generally presents without diarrhoea and is frequently associated with defects in the complement pathway leading to over-activation of complement. The major cause of paediatric aHUS is due to defects in complement factor H, a regulatory protein that limits complement activation. Mutations in CFH that are both dominant and recessive have been described. There are now over 10 other genes that have been described in aHUS with around 40% of sporadic cases of aHUS without an identified genetic cause. Clinically patients often present acutely with an infectious prodrome, and may require supportive haemodialysis and transfusion. Children occasionally have extra renal manifestations