Marginal zone lymphomas: a consensus practice statement from the Australasian Lymphoma Alliance.

Marginal zone lymphomas (MZLs) are a rare, indolent group of non-Hodgkin lymphomas with different diagnostic, genetic and clinical features and therapeutic implications. The most common is extranodal MZL of mucosa-associated lymphoid tissue, followed by splenic MZL and nodal MZL. Patients with MZL generally have good outcomes with long survival rates but frequently have a relapsing/remitting course requiring several lines of therapy. The heterogeneous presentation and relapsing course present the clinician with several diagnostic and therapeutic challenges. This position statement presents evidence-based recommendations in the setting of Australia and New Zealand.

The Fight Tumour Blindness Registry: Efficient capture of high-quality real-world data in uveal melanoma.

OBJECTIVE: To describe the development of a web-based data collection tool to track the management and outcomes of uveal melanoma patients. DESIGN: Description of a clinical registry. PARTICIPANTS: Patients with uveal melanoma. METHODS: A panel of expert ocular oncologists, with input from other relevant specialties and individuals with expertise in registry development, collaborated to formulate a minimum data set to be collected to track patient centred, real-world outcomes in uveal melanoma. This data set was used to create the Fight Tumour Blindness! (FTB!) registry within Save Sight Registries. RESULTS: The data set to be collected includes patient demographics and medical history, baseline visit, follow-up visit including tumour treatment, metastatic staging and surveillance, pathology, and patient-reported questionnaires. The inbuilt mechanisms to ensure efficient and complete data collection are described. CONCLUSIONS: The FTB! registry can be used to monitor outcomes for patients with uveal melanoma. It allows benchmarking of outcomes and comparisons between different clinics and countries.

Recognition and epileptology of protracted CLN3 disease.

OBJECTIVE: This study was undertaken to analyze phenotypic features of a cohort of patients with protracted CLN3 disease to improve recognition of the disorder. METHODS: We analyzed phenotypic data of 10 patients from six families with protracted CLN3 disease. Haplotype analysis was performed in three reportedly unrelated families. RESULTS: Visual impairment was the initial symptom, with onset at 5-9 years, similar to classic CLN3 disease. Mean time from onset of visual impairment to seizures was 12 years (range = 6-41 years). Various seizure types were reported, most commonly generalized tonic-clonic seizures; focal seizures were present in four patients. Progressive myoclonus epilepsy was not seen. Interictal electroencephalogram revealed mild background slowing and 2.5-3.5-Hz spontaneous generalized spike-wave discharges. Additional interictal focal epileptiform discharges were noted in some patients. Age at death for the three deceased patients was 31, 31, and 52 years. Molecular testing revealed five individuals were homozygous for c.461-280_677 + 382del966, the "common 1-kb" CLN3 deletion. The remaining individuals were compound heterozygous for various combinations of recurrent pathogenic CLN3 variants. Haplotype analysis demonstrated evidence of a common founder for the common 1-kb deletion. Dating analysis suggested the deletion arose approximately 1500 years ago and thus did not represent cryptic familial relationship in this Australian cohort. SIGNIFICANCE: We highlight the protracted phenotype of a disease generally associated with death in adolescence, which is a combined focal and generalized epilepsy syndrome with progressive neurological deterioration. The disorder should be suspected in an adolescent or adult patient presenting with generalized or focal seizures preceded by progressive visual loss. The common 1-kb deletion has been typically associated with classic CLN3 disease, and the protracted phenotype has not previously been reported with this genotype. This suggests that modifying genetic factors may be important in determining this somewhat milder phenotype and identification of these factors should be the subject of future research.

Muscle biopsy practices in the evaluation of neuromuscular disease: A systematic literature review.

AIMS: Muscle biopsy techniques range from needle muscle biopsy (NMB) and conchotome biopsy to open surgical biopsy. It is unknown whether specific biopsy techniques offer superior diagnostic yield or differ in procedural complication rates. Therefore, we aimed to compare the diagnostic utility of NMB, conchotome and open muscle biopsies in the assessment of neuromuscular disorders. METHODS: A systematic literature review of the EMBASE and Medline (Ovid) databases was performed to identify original, full-length research articles that described the muscle biopsy technique used to diagnose neuromuscular disease in both adult and paediatric patient populations. Studies of any design, excluding case reports, were eligible for inclusion. Data pertaining to biopsy technique, biopsy yield and procedural complications were extracted. RESULTS: Sixty-four studies reporting the yield of a specific muscle biopsy technique and, or procedural complications were identified. Open surgical biopsies provided a larger tissue sample than any type of percutaneous muscle biopsy. Where anaesthetic details were reported, general anaesthesia was required in 60% of studies that reported open surgical biopsies. Percutaneous biopsies were most commonly performed under local anaesthesia and despite the smaller tissue yield, moderate- to large-gauge needle and conchotome muscle biopsies had an equivalent diagnostic utility to that of open surgical muscle biopsy. All types of muscle biopsy procedures were well tolerated with few adverse events and no scarring complications were reported with percutaneous sampling. CONCLUSIONS: When a histological diagnosis of myopathy is required, moderate- to large-gauge NMB and the conchotome technique appear to have an equivalent diagnostic yield to that of an open surgical biopsy.

IgG4-related ophthalmic disease in association with adult-onset asthma and periocular xanthogranuloma: a case report.

A 54-year-old male presented with a three-year history of bilateral upper eyelid and peri-orbital swelling and adult-onset asthma. Histopathology of a left orbital biopsy showed lymphoid follicles with foamy macrophages and Touton giant cells. Clinical, histological and radiological features were consistent with adult-onset asthma and periocular xanthogranuloma. Treatment with rituximab led to a complete clinical and radiological remission. Nine years later, his condition relapsed with a biopsy of the left orbit and lacrimal gland demonstrating features of IgG4-related disease and adult-onset asthma and periocular xanthogranuloma. Immunohistochemistry showed increased numbers of IgG4+ plasma cells (290 per high power field) and an elevated IgG4+/IgG+ plasma cell ratio of 480%. Involvement by both disorders in the orbit and ocular adnexa of a single patient has not previously been reported in the literature, to the best of our knowledge, and suggests a possible aetiologic or pathophysiologic association.

Eosinophilic myositis: could it be an adult-onset dystrophy?

A 40-year-old woman presented with a 20 kg weight loss and asymmetrical hip and shoulder girdle muscle weakness; she had a raised serum creatine kinase and mild peripheral blood eosinophilia. There was no evidence of a parasitic infection or vasculitis. A muscle biopsy showed eosinophilic myositis. Following treatment with oral corticosteroid, methotrexate and intravenous immunoglobulin infusion, her weakness initially mildly improved and her serum creatine kinase reduced. However, despite continued immunosuppression her condition progressed over 3 years. The pattern of muscle weakness suggested a muscular dystrophy. Genetic testing confirmed heterozygous calpain mutations consistent with limb girdle muscular dystrophy type 2A.

Orbital giant cell myositis is an unusual and potentially lethal cause of bilateral ophthalmoplegia - A case report and literature review.

We present a case of orbital giant cell myositis (OGCM), presenting with bilateral subacute progressive ophthalmoplegia and optic nerve dysfunction. An early extraocular muscle biopsy confirmed the diagnosis and guided appropriate management. Comprehensive investigation excluded any underlying systemic disease, including myocarditis. Twenty two months after presentation, the patient remains well on azathioprine with complete resolution of orbital signs.

Biopsy for molecular risk stratification in uveal melanoma: Yields and molecular characteristics in 119 patients.

BACKGROUND: Prognostic cytological and molecular features of uveal melanoma have been well researched and are essential in management. Samples can be obtained in vivo through fine needle aspirate biopsy, vitrector cutter, forceps or post-enucleation for off-site testing. This study aims to examine cytological and chromosome microarray yields of these samples. METHODS: A retrospective cohort analysis of 119 uveal melanoma biopsies submitted to our laboratory. Samples included those taken in vivo (n = 57) and post-enucleation (n = 62). Patient and tumour features were collected including age, sex, primary tumour location, basal diameter and tumour height. Prognostic outcomes measured include cell morphology, chromosomal status and immunohistochemistry. RESULTS: Post-enucleation biopsies accounted for just over half of our samples (52%). Post-enucleation samples had a more successful genetic yield than in vivo biopsies (77% vs. 50%, p = 0.04) though there was no difference for cytological yields. There was no difference in cytological or microarray yields between instruments. The vitrector biopsy group had the smallest tumour thickness (5 mm vs. 10 mm [fine-needle aspirate biopsy], p = 0.003). There was a strong correlation between monosomy 3, BAP1 aberrancy and epithelioid cell type in post-enucleation samples (Tb  = 0.742, p = 0.005). However, epithelioid morphology was not associated with either monosomy 3 (p = 0.07) or BAP1 aberrancy (p = 0.24) for in vivo biopsies. CONCLUSIONS: All three biopsy instruments provide similar cytological yields as post-enucleation sampling, although post-enucleation samples had a more successful chromosome microarray yield. Epithelioid cytomorphology alone is insufficient for prognostication in in vivo biopsies, immunohistochemistry would be a useful surrogate test.

Matured Myofibers in Bioprinted Constructs with In Vivo Vascularization and Innervation.

For decades, the study of tissue-engineered skeletal muscle has been driven by a clinical need to treat neuromuscular diseases and volumetric muscle loss. The in vitro fabrication of muscle offers the opportunity to test drug-and cell-based therapies, to study disease processes, and to perhaps, one day, serve as a muscle graft for reconstructive surgery. This study developed a biofabrication technique to engineer muscle for research and clinical applications. A bioprinting protocol was established to deliver primary mouse myoblasts in a gelatin methacryloyl (GelMA) bioink, which was implanted in an in vivo chamber in a nude rat model. For the first time, this work demonstrated the phenomenon of myoblast migration through the bioprinted GelMA scaffold with cells spontaneously forming fibers on the surface of the material. This enabled advanced maturation and facilitated the connection between incoming vessels and nerve axons in vivo without the hindrance of a scaffold material. Immunohistochemistry revealed the hallmarks of tissue maturity with sarcomeric striations and peripherally placed nuclei in the organized bundles of muscle fibers. Such engineered muscle autografts could, with further structural development, eventually be used for surgical reconstructive purposes while the methodology presented here specifically has wide applications for in vitro and in vivo neuromuscular function and disease modelling.

Ptosis, ophthalmoplegia and corneal endothelial disease - ocular manifestations of mitochondrial disease.

PURPOSE: To describe two patients with bilateral ptosis, ophthalmoplegia, cataracts and corneal endothelial disease requiring corneal transplantation. OBSERVATIONS: Histopathological analysis of muscle biopsy samples from both patients identified features consistent with a mitochondrial cytopathy. A single multigenic mitochondrial deoxyribonucleic acid (DNA) deletion was detected in the first patient. Pathogenic mutations in the POLG gene which codes for mitochondrial DNA polymerase, tasked with replicating the mitochondrial genome were identified in the second patient. CONCLUSION: The collection of clinical features present in both cases described can be explained by a diagnosis of mitochondrial disease. IMPORTANCE: Corneal endothelial disease, in addition to ptosis, ophthalmoplegia, cataract, pigmentary retinopathy and optic atrophy should be recognised as a feature of mitochondrial disease.

A Case Series of Intramuscular Orbital Choristomatous Cysts.

Intramuscular choristomatous cystic lesions within the orbit are rare but may require removal due to their volume effects. The authors describe 2 such cases of intramuscular cysts in adult patients. Both patients presented with symptoms due to local mass effects with swelling, proptosis and diplopia. Imaging confirmed cystic intramuscular masses. Surgical removal involved intraoperative decompression of the cyst to aid dissection with excision of some muscle fibers. Histology confirmed a keratinized stratified squamous lined dermoid cyst within lateral rectus for case 1 and stratified squamous non-keratinized conjunctival epithelium (simple primary conjunctival cyst) within inferior oblique for case 2.

Eyelid basal cell carcinoma with neuroendocrine differentiation: a case report and literature review.

Basal cell carcinoma (BCC) is the most common type of malignant tumor in the periocular region. BCCs with neuroendocrine differentiation in the periocular region, however, have not been described in the literature.We present a retrospective case review of a patient with an eyelid BCC with neuroendocrine differentiation. Demographical, clinical, radiological, surgical, histological, and follow-up data are presented.The patient presented with a slow-growing lesion of the eyelid with associated epiphora and dull ache. Initial incisional biopsy of the lesion revealed an infiltrating carcinoma composed of epithelial cells. Immunohistochemistry showed that the tumor was positive for p40, Ber-Ep4, neuron specific enolase (NSE), chromogranin A, CD56 (NCAM), and synaptophysin. The pathology from the margin-controlled excision showed basosquamous cell carcinoma with neuroendocrine differentiation. Tumor recurrence was not detected clinically at the post-operative six-month review.BCC with neuroendocrine marker positivity represents an important diagnostic differential for rare eyelid carcinomas such as primary cutaneous neuroendocrine carcinoma and metastatic small cell carcinoma that have a poor prognosis. The prognostic importance of neuroendocrine marker positivity in BCCs is uncertain. The present case provides further evidence for neuroendocrine differentiation in BCCs.

Persistent hiccups and Horner's syndrome in a case of primary CNS lymphoma with diffuse cerebral, hypothalamic and lateral brainstem involvement - An exercise in clinical neuroanatomy.

We present a case of a 42-year-old male presenting with persistent hiccups and a Horner's syndrome, among other symptoms and signs of hypothalamic and brainstem dysfunction. He had a biopsy-proven diffuse infiltrative large primary CNS B-cell lymphoma involving the left fronto-temporal hemisphere, diencephalon and brainstem. The aim of this case report is to highlight key clinical and neuro-anatomical correlations that bring light to the art of the clinical examination.

Is it Pompe Disease? Australian diagnostic considerations.

Pompe Disease is a spectrum disorder with an evolving phenotype in which diagnostic delay is common. Contributing factors include the rarity of the disorder, its wide clinical spectrum, signs and symptoms that overlap with those of other neuromuscular disorders, variable diagnostic approaches, lack of awareness of the clinical manifestations and difficulties in completing the diagnostic inventory. International updates and recommendations have been published providing diagnostic guidelines and management criteria. However, questions remain in the Australian setting. A panel (two neurologists, one clinical geneticist) reviewed the literature, examined clinical questions of relevance to the Australian setting, and developed a framework for the guidance. A wider panel, comprising the initial panel plus eight additional members, critiqued the framework and contributed clinical guidance within the scope of their respective areas of clinical expertise. The resultant expert consensus recommendations build on currently available data to propose an appropriate management framework incorporating the diagnosis, classification, therapeutic approach, multidisciplinary care, and on-going monitoring of patients with Pompe Disease in the Australian setting. It is hoped that diagnostic delay can be reduced with appropriate recourse to evidence-based insights and practical advice on diagnosis and management tailored to the Australian setting.

Lymphoma, a great imitator in neurology.

The title "great imitator" refers to conditions which can cause varied manifestations and mimic many diseases. Lymphoma is worthy of this title. We describe three cases of lymphoma in which lymphoma mimicked other diseases causing neurological dysfunction, specifically sarcoidosis, vasculitis and infection respectively. Case 1 was a 66-year-old man with subacute progressive diplopia and gait disturbance and investigations revealing a supratentorial para-falcine soft tissue lesion, mid-thoracic cord enhancement and right axillary mass and an elevated serum ACE. Right axillary mass core biopsy was diagnostic of Burkitt lymphoma. Case 2 was a 50-year-old man with several weeks of constitutional symptoms and development of lower limb weakness and numbness, urinary retention and confusion while in hospital. MRI brain demonstrated multi-territory cerebral infarcts. Intravascular lymphoma was diagnosed on random skin biopsy. Case 3 was a 65-year-old man with several weeks of headache and diplopia on a background of previously treated Burkitt lymphoma. CSF analysis showed a lymphocytic pleocytosis and markedly low glucose with cytologic analysis negative for malignancy. Investigations for an infective cause were negative. FDG-PET demonstrated marked, disseminated spinal and cranial leptomeningeal disease and a multi-focal, intra-dural relapse of Burkitt lymphoma was diagnosed. The varied manifestations in our cases demonstrate the ability for lymphoma to mimic infective, inflammatory, granulomatous (including sarcoidosis) and neoplastic aetiologies. An elevated serum ACE appears insufficiently diagnostic to confirm sarcoidosis and tissue for histological examination should be sought whenever possible. When the diagnosis is uncertain, the possibility of this great imitator should be considered, especially for multi-focal disease.

Multiple myeloma manifesting as an ocular salmon patch - a case report.

Multiple myeloma (MM) is the second most prevalent hematologic malignancy after non-Hodgkin lymphoma and is currently considered incurable. Clinical ophthalmic manifestations of MM are rare but at the same time diverse. Ocular surface manifestations of multiple myeloma are uncommon. Conjunctival 'salmon patch' is a typical ocular surface ophthalmological sign with a distinct set of differential diagnoses, including most often ocular adnexal lymphoma. This case report presents a 33-year-old female with a relapse of MM manifesting as a conjunctival 'salmon patch'. The patient initially responded well to medical management including high dose melphalan supported by a third autologous stem cell transplantation (ASCT) and did not require further surgical excision of the ocular lesion. It is suggested that MM should be included in the differential diagnosis of 'salmon patch' conjunctival lesions.

Lacrimal Gland Orbital Lobe Cysts Associated With Lymphoid Hyperplasia or Mucosa-Associated Lymphoid Tissue Lymphoma in Patients With Chronic Autoimmune Disease.

Large cysts in the orbital lobe of the lacrimal gland are rare and are associated with Sjögren syndrome and B-cell mucosa-associated lymphoid tissue lymphoma. The authors describe 4 new cases of large orbital lobe lacrimal gland cysts. The first 2 patients, both with Sjögren syndrome, had unilateral cysts associated with chronic inflammation. Mucosa-associated lymphoid tissue lymphoma was also identified in the cyst wall of the second case and could not be completely excluded in the first case. The third patient, with a history of rheumatoid arthritis, had bilateral cysts, again associated with mucosa-associated lymphoid tissue lymphoma. The fourth patient, with no history of systemic disease, had a unilateral cyst associated with reactive lymphoid hyperplasia. Finally, the authors report the long-term outcomes of 3 previously reported cases.