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.

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.

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.

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.

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.

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.

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.

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.

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.

Primary orbital melanoma: a case series and literature review.

Primary orbital melanoma (POM) is a very rare condition. We report further four cases and review all previously reported cases. We present a multicentre retrospective review of patients with POM. Clinical, radiological, surgical, histological, and follow-up data is presented. Four patients with POM were identified between 2000 and 2013. All presented with proptosis and diplopia without reduced vision. Two had known pre-existing blue cell naevi. All were stage T1N0M0. All underwent exenteration with adjuvant radiotherapy. All are disease free at follow-up durations of 24-151 months. The present three cases and review of all cases in the literature suggest a higher likelihood of disease-free survival from primary exenteration (7/8 disease-free survival, 1/8 death from metastatic disease) than wide local excision (7/16 disease-free survival, 9 recurrence or metastasis of whom 4 died). Adjuvant radiotherapy may additionally improve outcomes.

Materials in the vitreous during cataract surgery: nature and incidence, with two cases of histological confirmation.

BACKGROUND: To identify and classify materials in the vitreous observed during phacoemulsification cataract surgery (phaco). DESIGN: Prospective, consecutive, observational case series at one ophthalmic day surgery in Sydney, Australia. PARTICIPANTS: A total of 767 consecutive phaco cases. Cases were excluded if there was posterior capsule rupture or vitreous loss intraoperatively. METHODS: For each patient, age, gender, baseline corrected distance visual acuity, presence of pseudoexfoliation, nuclear sclerosis grade and phacoemulsification ultrasound time were recorded. The relationship between these variables and materials in the vitreous was evaluated with regression analysis. Two patients with materials in the vitreous developed an acute intraoperative rock-hard eye syndrome. In these two patients, pars plana needle aspiration of retrolenticular fluid was performed to re-establish normal intraocular pressure. Histology was undertaken to compare this fluid with known lens material retrieved from the Fluid Management System bags in two unrelated cases. MAIN OUTCOME MEASUREMENTS: Presence of materials in the vitreous during phaco. RESULTS: Materials in the vitreous were observed in either Berger's space or the anterior vitreous in 386 eyes (50.3% of cases); the majority was putatively lens material (46.5% of all cases). Pigment and ophthalmic viscoelastic device were seen in the anterior vitreous in 9.8% and 1.7% of cases, respectively. Logistic regression analysis demonstrated that higher nuclear sclerosis grade (P = 0.025), male gender (P = 0.003) and greater age (P = 0.016) were predictive of the presence of materials in the vitreous. Histological assessment with light microscopy and birefringence techniques identified the materials in the vitreous as lens material. CONCLUSION: Materials in the vitreous were seen in 50.3% of phaco cases. It has been histologically demonstrated that lens materials can be introduced into the anterior vitreous during phaco.

IgG4-related ophthalmic disease. Part I: background and pathology.

PURPOSE: To review the current state of knowledge of IgG4-related ophthalmic disease (IgG4-ROD). METHODS: A review of the literature and personal experience of the authors. RESULTS: IgG4-related disease is a recently recognized fibroinflammatory disorder that may affect 1 or more organs. It is characterized by lymphoplasmacytic infiltrates with large numbers of IgG4 positive plasma cells, storiform fibrosis, obliterative phlebitis, and eosinophil infiltration as well as peripheral eosinophilia, and in some cases, elevated serum levels of IgG4. These features are not always seen, and the diagnosis should be made by integrating clinical, imaging, and histopathological data, with reference to recently defined diagnostic criteria. IgG4-ROD forms a significant proportion of what has previously been labeled "idiopathic orbital inflammation" or reactive lymphoid hyperplasia. Orbital disease may occur alone, at the same time as disease elsewhere, or metachronously with systemic disease. Although almost any ocular adnexal tissue may be affected, there are several more common recognizable patterns of IgG4-ROD: 1) sclerosing dacryoadenitis; 2) enlargement of orbital nerves (most commonly the infraorbital nerve) associated with orbital myositis and lacrimal gland disease, often in combination with paranasal sinus disease, eosinophilia, and systemic involvement; and 3) sclerosing orbital inflammation. CONCLUSIONS: Patients presenting with orbital inflammatory lesions should have biopsies obtained whenever possible. The examining pathologist should routinely look for features of IgG4-ROD, and if found, the patient should be investigated for other organ involvement. Early treatment may prevent destructive changes in affected tissues.

IgG4-Related Ophthalmic Disease. Part II: Clinical Aspects.

PURPOSE: To review the current state of knowledge of IgG4-related ophthalmic disease (IgG4-ROD). METHODS: A review of the literature and personal experience of the authors. RESULTS: IgG4-related disease is a recently recognized fibroinflammatory disorder that may affect 1 or more organs. It is characterized by lymphoplasmacytic infiltrates with large numbers of IgG4 positive plasma cells, storiform fibrosis, obliterative phlebitis, and eosinophil infiltration as well as peripheral eosinophilia, and in some cases, elevated serum levels of IgG4. These features are not always seen, and the diagnosis should be made by integrating clinical, imaging, and histopathological data, with reference to recently defined diagnostic criteria. IgG4-ROD forms a significant proportion of what has previously been labeled "idiopathic orbital inflammation" or reactive lymphoid hyperplasia. Orbital disease may occur alone, at the same time as disease elsewhere, or metachronously with systemic disease. Although almost any ocular adnexal tissue may be affected, there are several commoner recognizable patterns of IgG4-ROD: (1) sclerosing dacryoadenitis; 2) enlargement of orbital nerves (most commonly the infraorbital nerve) associated with orbital myositis and lacrimal gland disease, often in combination with paranasal sinus disease, eosinophilia, and systemic involvement; and 3) sclerosing orbital inflammation. Patients with IgG4-ROD should be investigated and monitored for other organ involvement. Some patients with IgG4-related disease may develop lymphoma, usually marginal zone lymphoma of mucosa-associated lymphoid tissue type. Treatment of IgG4-ROD includes the use of corticosteroids and other immunosuppressants. Rituximab has been shown to be very effective. Longer term studies on the natural course and treatment of IgG4-ROD are needed. CONCLUSIONS: Patients presenting with orbital inflammatory lesions should have biopsies obtained whenever possible. The examining pathologist should routinely look for features of IgG4-ROD, and if found, the patient should be investigated for other organ involvement. Early treatment may prevent destructive changes in affected tissues.

Malignant melanoma of the lacrimal drainage apparatus complicating conjunctival melanoma.

PURPOSE: Melanoma of the conjunctiva may occasionally involve the lacrimal drainage apparatus (LDA). This makes clinical management difficult. The authors describe 5 cases of conjunctival melanoma with LDA disease and make recommendations about its management. METHODS: Retrospective review of case notes and histopathology reports. RESULTS: Five cases of LDA melanoma arising in patients with conjunctival melanoma are described. All 5 had orbital exenteration as part of their treatment. Melanoma of the LDA was clinically present at the time of exenteration in 1 case, found unexpectedly in 2 cases, and developed subsequent to exenteration in 2 cases. One patient died within 8 months of exenteration from metastatic melanoma. Two patients were disease free 3 and 5 years after exenteration. One patient developed metastasis in the parotid gland 4 years after exenteration but remained disease free 7 years after exenteration. One more patient has had a local recurrence in the maxilla and lateral nasal wall 4 years after exenteration, and after resection of that lesion and radiotherapy is disease free after 18 months. Seventeen patients underwent orbital exenteration for conjunctival melanoma over the period 1996-2013 at the authors'institution, with 5 having or developing LDA disease (29%). In the same period, there were 52 patients with conjunctival melanoma overall, with LDA involvement occurring in 5 of 52 patients (9.6%). CONCLUSIONS: Melanoma of the LDA may complicate conjunctival melanoma in a significant percentage of cases having orbital exenteration. The surgical technique for orbital exenteration in patients with conjunctival melanoma should take this into account by intentionally removing the lacrimal sac and upper nasolacrimal duct as well as the lacrimal canaliculi. If melanoma is found in the LDA, consideration should be given to wider en bloc excision of the LDA.

Capture of somatic mtDNA point mutations with severe effects on oxidative phosphorylation in synaptosome cybrid clones from human brain.

Mitochondrial DNA (mtDNA) is replicated throughout life in postmitotic cells, resulting in higher levels of somatic mutation than in nuclear genes. However, controversy remains as to the importance of low-level mtDNA somatic mutants in cancerous and normal human tissues. To capture somatic mtDNA mutations for functional analysis, we generated synaptosome cybrids from synaptic endings isolated from fresh hippocampus and cortex brain biopsies. We analyzed the whole mtDNA genome from 120 cybrid clones derived from four individual donors by chemical cleavage of mismatch and Sanger sequencing, scanning around two million base pairs. Seventeen different somatic point mutations were identified, including eight coding region mutations, four of which result in frameshifts. Examination of one cybrid clone with a novel m.2949_2953delCTATT mutation in MT-RNR2 (which encodes mitochondrial 16S rRNA) revealed a severe disruption of mtDNA-encoded protein translation. We also performed functional studies on a homoplasmic nonsense mutation in MT-ND1, previously reported in oncocytomas, and show that both ATP generation and the stability of oxidative phosphorylation complex I are disrupted. As the mtDNA remains locked against direct genetic manipulation, we demonstrate that the synaptosome cybrid approach can capture biologically relevant mtDNA mutants in vitro to study effects on mitochondrial respiratory chain function.