Nikki R Adler

Metastatic pathways in patients with cutaneous melanoma

Metastasis represents the end product of an elaborate biological process, which is determined by a complex interplay between metastatic tumour cells, host factors and homoeostatic mechanisms. Cutaneous melanoma can metastasize haematogenously or lymphogenously. The three predominant models that endeavour to explain the patterns of melanoma progression are the stepwise spread model, the simultaneous spread model and the model of differential spread. The time course to the development of metastases differs between the different metastatic routes. There are several clinical and histopathological risk factors for the different metastatic pathways. In particular, patient sex and the anatomical location of the primary tumour influence patterns of disease progression. There is limited existing evidence regarding the relationship between tumour mutation status, other diagnostic and prognostic biomarkers and the metastatic pathways of primary cutaneous melanoma. This knowledge gap needs to be addressed to better identify patients at high risk of disease recurrence and personalize surveillance strategies.

Piperacillin-tazobactam-induced linear IgA bullous dermatosis presenting clinically as Stevens-Johnson syndrome/toxic epidermal necrolysis overlap.

Linear IgA bullous dermatosis (LABD) is a subepidermal autoimmune bullous disease characterized by linear IgA deposition at the basement membrane zone, which is visualized by direct immunofluorescence. Patients with LABD typically present with widespread vesicles and bullae; however, this is not necessarily the case, as the clinical presentation of this disease is heterogeneous. LABD clinically presenting as Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) is an infrequent, yet well‐described phenomenon. Most cases of LABD are idiopathic, but some cases are drug‐induced. Multiple drugs have been implicated in the development of LABD. We report a case of piperacillin–tazobactam‐induced LABD presenting clinically as SJS/TEN overlap. This is the first reported case of a strong causal association between piperacillin‐tazobactam and the development of LABD.

Drug‐induced liver injury is frequently associated with severe cutaneous adverse drug reactions: experience from two Australian tertiary hospitals

Drug‐induced liver injury (DILI) can be associated with certain cutaneous adverse drug reaction (cADR).

Nodular melanoma is less likely than superficial spreading melanoma to be histologically associated with a naevus

Objectives: To determine the frequency of naevus‐associated melanoma among superficial spreading and nodular subtypes; and to investigate associations between naevus‐associated melanoma and other clinico‐pathological characteristics.

Tumour mutation status and sites of metastasis in patients with cutaneous melanoma

Background:Cutaneous melanoma can metastasise haematogenously and/or lymphogenously to form satellite/in-transit, lymph node or distant metastasis. This study aimed to determine if BRAF and NRAS mutant and wild-type tumours differ in their site of first tumour metastasis and anatomical metastatic pathway.Methods:Prospective cohort of patients with a histologically confirmed primary cutaneous melanoma at three tertiary referral centres in Melbourne, Australia from 2010 to 2015. Multinomial regression determined clinical, histological and mutational factors associated with the site of first metastasis and metastatic pathway.Results:Of 1048 patients, 306 (29%) developed metastasis over a median 4.7 year follow-up period. 73 (24%), 192 (63%) and 41 (13%) developed distant, regional lymph node and satellite/in-transit metastasis as the first site of metastasis, respectively. BRAF mutation was associated with lymph node metastasis (adjusted RRR 2.46 95% CI 1.07–5.69, P=0.04) and sentinel lymph node positivity (adjusted odds ratio [aOR] OR 1.55, 95% CI 1.14–2.10, P=0.005). BRAF mutation and NRAS mutation were associated with increased odds of developing liver metastasis (aOR 3.09, 95% CI 1.49–6.42, P=0.003; aOR 3.17, 95% CI 1.32–7.58, P=0.01) and central nervous system (CNS) metastasis (aOR 4.65, 95% CI 2.23–9.69, P<0.001; aOR 4.03, 95% CI 1.72–9.44, P=0.001). NRAS mutation was associated with lung metastasis (aOR 2.44, 95% CI 1.21–4.93, P=0.01).Conclusions:BRAF mutation was found to be associated with lymph node metastasis as first metastasis and sentinel lymph node positivity. BRAF and NRAS mutations were associated with CNS and liver metastasis and NRAS mutation with lung metastasis. If these findings are validated in additional prospective studies, a role for heightened visceral organ surveillance may be warranted in patients with tumours harbouring these somatic mutations.

Intravascular large B cell lymphoma with haemophagocytic syndrome: a double lethal masquerade.

A67-year-oldChinesemanwithminimalmedical history presented with a 4-week history of fevers, weight loss and functional decline. The only positive physical findings included pyrexia (>38°C), hypoxia (SpO2 90%on air), sinus tachycardia, hypotension (80/50mmHg) and mild splenomegaly. The working diagnosis was undifferentiated septic shock; therefore, he was treated in the Intensive Care Unit with inotropes, piperacillin-tazobactam, ciprofloxacin and azithromycin. Preliminary investigations are listed in Table 1. Computed tomography of pulmonary arteries to investigate the cause of persistent hypoxia demonstrated a small left-lower lobe segmental pulmonary embolus. Subsequent venous Doppler scan confirmed a right posterior tibial vein thrombus as a possible source. Abdominal computed tomography to investigate for a possible focus of infection demonstrated splenic lesions highly suspicious for embolic infarcts. Diagnostic possibilities at this stage included infective endocarditis, prothrombotic states from a possible malignancy and vasculitides. However, an exhaustive screen for infective and autoimmune/rheumatological aetiologies was unremarkable (Table 1). Observation of persistently elevated lactate and increasing hyperferritinaemia (Table 1) eventually prompted a bone marrow aspirate and trephine biopsy (Fig. ), which demonstrated haemophagocytic lymphohistiocytosis without an obvious haematologicalmalignancy. Furtherwork-up for infective aetiologies was also negative. However, close scrutiny of trephine sections established the final diagnosis of intravascular large B cell lymphoma (IVLBCL) (Fig. ). Treatment with rituximab, cyclophosphamide and dexamethasone was instituted immediately, which resulted in improvement in clinical and biochemical parameterswithinweeks. The patient was subsequently discharged and remained well after six cycles of consolidation chemotherapy. Our case demonstrates significant challenges in the work-up of patients with fever of unknown origin (FUO) and in establishing the diagnosis of IVLBCL. IVLBCL is a rare subtype of extranodal diffuse large B cell lymphoma, which is characterised by intravascular proliferation of neoplastic lymphocytes. The median age of presentation is 70 years, and it affects males and females equally. Patients commonly present with functional decline and FUO, often displaying a rapidly progressive clinical course and disseminated disease. Due to non-specific clinical manifestations, an exhaustive quest for underlying aetiologies often contributes to a delayed or post-mortem diagnosis. A timely diagnosis resulting in patient survival is uncommon. An ‘Asian’ variant of IVLBCL, as in our case, is preferentially associated with hepatosplenomegaly, thrombocytopenia and anaemia. Contrary to the ‘Western’ variant, Asian patients rarely exhibit the classical cutaneous or central nervous system manifestations; however, reticuloendothelial system and bone marrow involvement are common. Moreover, the ‘Asian’ variant is frequently associated with haemophagocytic lymphohistiocytosis. Notwithstanding its intravascular nature, the diagnosis is difficult as IVLBCL is almost always absent in peripheral blood by morphologic examination. However, occasional atypical circulating cells have been observed. Bone marrow biopsy is usually required, and the presence of CD20+ lymphoid cells within the lumen of blood vessels is essential for the diagnosis. As IVLBCL is often an aggressive disease, treatment consists of anthracycline-based chemotherapy regimen, such as cyclophosphamide, doxorubicin, vincristine and prednisone with the addition of rituximab. In order to achieve a timely diagnosis and management, physicians should consider the possibility of IVLBCL and/or haemophagocytic syndrome in patients who present with FUO, in whom the diagnosis remains unclear after more common aetiologies have been excluded. Brief Communications

Clinicopathological characteristics and prognosis of patients with multiple primary melanomas

This narrative review provides an evidence-based overview of existing literature on the epidemiology, clinicopathological characteristics and prognostic outcomes of tumours arising in patients with multiple primary melanomas (MPM). PubMed and MEDLINE were searched for original research papers and review articles from 2000 to 2016 using the term ‘multiple primary melanoma.’ Population-wide increases in life expectancy, advances in early detection and increasing incidence of melanoma give rise to an expanding group of patients that are at an increased risk of developing subsequent primary tumours. This article is protected by copyright. All rights reserved.

Recent advances in the understanding of severe cutaneous adverse reactions

Severe cutaneous adverse reactions (SCARs) encompass a heterogeneous group of delayed hypersensitivity reactions, which are most frequently caused by drugs. Our understanding of several aspects of SCAR syndromes has evolved considerably over the last decade. This review explores evolving knowledge of the immunopathogenic mechanisms, pharmacogenomic associations, in vivo and ex vivo diagnostics for causality assessment, and medication cross‐reactivity data related to SCAR syndromes. Given the rarity and severity of these diseases, multidisciplinary collaboration through large international, national and/or multicentre networks to collect prospective data on patients with SCAR syndromes should be prioritized. This will further enhance a systematized framework for translating epidemiological, clinical and immunopathogenetic advances into preventive efforts and improved outcomes for patients.

Adverse Drug Reactions Reported by Healthcare Professionals: Reaction Characteristics and Time to Reporting

We describe adverse drug reaction (ADR) reporting characteristics and factors contributing to length of time to report by healthcare professionals. This is a retrospective study of voluntary reports to an Australian healthcare ADR Review Committee over a 2‐year period (2015–2016). Descriptive and univariate models were used for outcomes, employing standardized ADR definitions. Hospital pharmacists reported 84.8% of the 555 ADRs: 70.3% were hospital onset reactions, and 71.7% were at least of moderate severity. Immunologically mediated reactions were most commonly reported (409, 73.7%). The median time to submit an ADR report was 3 (interquartile range 1–10) days. Longer median times to reporting were associated with multiple implicated agents and delayed hypersensitivity reactions, especially severe cutaneous adverse reactions. A total of 650 medications were implicated that involved multiple agents in 165/555 (29.7%) reports. Antimicrobials were the most commonly implicated agents. Immunologically mediated reactions were most commonly associated with antimicrobials and radiocontrast agents (P < .0001, odds ratio [OR] 3.6, 95%CI 2.4–5.5, and P = .04, OR 4.2, 95%CI 1.2–18.2, respectively). Opioids and psychoactive medications were more commonly implicated in nonimmunological reported ADRs (P = .0002, OR 3.9, 95%CI 1.9–7.9, and P < .0001, OR 11.4, 95%CI 4.6–27.8, respectively). Due to the predominant reporting of immunologically mediated reactions, a targeted education program is being planned to improve identification and accuracy of ADR reports, with the overall aim of improved management to ensure quality service provision and patient safety.

Concordance of somatic mutational profile in multiple primary melanomas

This study aimed to determine the frequency and concordance of BRAF and NRAS mutation in tumours arising in patients with multiple primary melanoma (MPM). Patients with MPM managed at one of three tertiary referral centres in Melbourne, Australia, from 2010 to 2015 were included. Incident and subsequent melanomas underwent mutation testing. Cohens kappa (κ) coefficient assessed agreement between incident and subsequent primary melanomas for both BRAF and NRAS mutation status (mutant versus wild‐type). Mutation testing of at least two primary tumours from 64 patients was conducted. There was poor agreement for both BRAF and NRAS mutation status between incident and subsequent melanomas (κ = 0.10, 95% CI −0.10 to 0.42; κ = 0.06, 95% CI −0.10 to 0.57, respectively). In view of the low concordance in BRAF mutation status between incident and subsequent melanomas, mutational analysis of metastatic tissue, rather than of a primary melanoma, in patients with MPM should be used to guide targeted therapy.