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Lymphoma is the commonest orbital malignancy. The typical presentation is proptosis or swelling, which warrants imaging and confirmation by tissue biopsy. Enophthalmos is a much rarer clinical sign and if bilateral and symmetrical can often present late. We describe a patient who presented with bilateral enophthalmos and symptomatic, secondary entropion due to bilateral non-Hodgkin's lymphoma in which orbital fat was replaced by a monoclonal proliferation of small B cells. Low-dose orbital radiotherapy and entropion surgery relieved the patient's symptoms.

AimsTo examine whether the specific location of ocular adnexal lymphoma (OAL) and the American Joint Committee on Cancer (AJCC) TNM tumour stage are prognostic factors for mortality in the main OAL subtypes.MethodsClinical and survival data were retrospectively collected from seven international eye cancer centres. All patients from 1980 to 2017 with histologically verified primary or secondary OAL were included. Cox regression was used to compare the ocular adnexal tumour locations on all-cause mortality and disease-specific mortality.ResultsOAL was identified in 1168 patients. The most frequent lymphoma subtypes were extranodal marginal zone B-cell lymphoma (EMZL) (n=688, 59%); follicular lymphoma (FL) (n=150, 13%); diffuse large B-cell lymphoma (DLBCL) (n=131, 11%); and mantle cell lymphoma (MCL) (n=89, 8%). AJCC/TNM tumour-stage (T-stage) was significantly associated with disease-specific mortality in primary ocular adnexal EMZL and increased through T-categories from T1 to T3 disease. No associations between AJCC/TNM T-stage and mortality were found in primary ocular adnexal FL, DLBCL, or MCL. EMZL located in the eyelid had a significantly increased disease-specific mortality compared with orbital and conjunctival EMZL, in both primary EMZL and the full EMZL cohort. In DLBCL, eyelid location had a significantly higher disease-specific mortality compared with an orbital or lacrimal gland location.ConclusionDisease-specific mortality is associated with AJCC/TNM T-stage in primary ocular adnexal EMZL patients. Lymphoma of the eyelid has the highest disease-specific mortality in primary EMZL, and in the full cohort of EMZL and DLBCL patients.

PURPOSE Orbital amyloidosis of the extraocular muscles (EOMs) is a rare condition, and its clinicoradiological features are not well elucidated. This study describes the characteristic clinical signs, MRI features, and potential treatment options. METHODS Retrospective multicenter case series and literature review of EOM amyloidosis. RESULTS Five cases were identified for inclusion. Common clinical findings were diplopia, ophthalmoplegia, and proptosis. Systemic amyloidosis was more likely to present with multiple muscle involvement, but no particular pattern was observed with localized disease. On MRI, amyloid deposition was characterized as a heterogeneous intramuscular mass with T2 hypointensity and post contrast enhancement. Management is dependent on the extent of disease and functional impairment; options include surgical debulking and radiation therapy. CONCLUSION EOM amyloidosis is uncommon. The combination of clinical and radiologic findings described in this study should lead to its clinical suspicion.

In 1991, Genta and Haggitt described four patients with segmental ischemic colitis caused by idiopathic myointimal hyperplasia in the small mesenteric veins (IMHMV). There are now 33 published cases of IMHMV in the literature; however, this condition is still sufficiently rare that it poses a diagnostic challenge to pathologists and clinicians and is often clinically or histologically confused with inflammatory bowel disease (IBD) or ischemic colitis. IMHMV is characterized by intimal smooth muscle hyperplasia resulting in thickened small and medium‐sized mesenteric veins (with arterial sparing). Clinically, it presents with symptoms that mimic IBD, such as bloody diarrhea, abdominal pain, and weight loss. Surgical resection appears to be curative. The present case describes a 63‐year‐old Vietnamese man with cardiovascular risk factors who was diagnosed with IMHMV after many months of severe symptoms. A review of the current literature follows the case report., Idiopathic myointimal hyperplasia of the mesenteric veins (IMHMV) is an inflammatory bowel disease‐mimic, characterised by intimal smooth muscle hyperplasia resulting in thickened small and medium‐sized mesenteric veins (with arterial‐sparing). We describe a 63‐year‐old Vietnamese man with cardiovascular risk factors who was diagnosed with IMHMV after many months of severe symptoms. A review of the current literature, including 33 published cases of IMHMV, follows the case report.

Lacrimal gland pleomorphic adenomas (LGPA) are benign mixed tumors. Diagnosis is based on clinical and radiological findings which usually prompts complete excision of the lesion to minimise recurrence and a cumulative risk of malignant transformation. Necrosis in pleomorphic adenoma has been rarely reported in salivary gland PA, either spontaneously or due to iatrogenic interventions. Necrosis is suggestive of a malignant process and makes interpretation of histology specimens difficult. A 23 year old woman, while awaiting biopsy for a mass in the left lacrimal gland, which had been symptomatic for only several months, presented with acute pain and swelling of the left lateral lid. An incisional biopsy showed an inflamed lacrimal gland with focal necrosis and atypia of adjacent cytology and gland architecture. Subsequent excisional biopsy confirmed an LGPA with some inflammation but no necrosis. Necrosis may occur as an atypical presentation in LGPA.

Mixed tumour of the skin is a rare entity also known as chondroid syringoma and pleomorphic adenoma. These usually present as slow-growing skin nodules with a smooth surface, clear boundaries, and no ulceration. Case series exist describing pleomorphic adenomas in the periocular region including the lids and orbit, separate to the more familiar lacrimal gland pleomorphic adenoma. These may arise from accessory or ectopic lacrimal gland tissue but in the eyelids are more likely to arise from sweat glands in the skin. Histopathological analysis of these lesions is important to identify complete excision, minimising recurrences and in identifying rare but potential malignant transformation. We describe the clinical features and outcomes in three cases of pleomorphic adenoma with two at the medial canthus (including one recurrence) and one in the brow region.

A 23-year old man presented with a swelling medially in his left orbit. He had had bilateral retinoblastoma as an infant and was treated with bilateral enucleation, chemotherapy and radiotherapy. Histological examination confirmed the lesion to be leiomyosarcoma. A genetic defect in the RB1 tumour suppressor gene underlies the development of hereditary retinoblastoma and renders patients at substantially increased risk of developing subsequent non-ocular malignancies including soft tissue sarcomas. This risk is enhanced by radiotherapy particularly if administered before the age of one year. Awareness, by both patients and healthcare professionals, of this risk of secondary malignancy, is extremely important. Identification and aggressive investigation of new symptoms and signs may allow for the earlier detection of secondary malignancy which may, in turn, improve outcomes.

Purpose To report the histologic and clinical features of idiopathic orbital myositis (IOM) patients who underwent extraocular muscle (EOM) biopsy over 20 years, to provide the first methodical reference to the expected histopathologic findings, and to discuss the histopathologic differences from common differential diagnoses. Design Cohort study. Participants All patients with a diagnosis of IOM who underwent EOM biopsy from 2000 through 2019 were included. Patients who had a different final diagnosis were excluded. Methods Tissue samples of EOM and medical records of all participants were reviewed. Main Outcome Measures Histopathologic features of muscle biopsy, including tissue morphologic features and cellular composition. Results Thirteen patients met both inclusion and exclusion criteria, and their tissue samples were revisited. Nine patients showed histopathologic findings that suggested a conclusive diagnosis of IOM, and the study focused on them. The average age at presentation was 49 years, and 66.7% of patients were women. The most commonly biopsied EOM was the medial rectus (44.4%). The most common indications for biopsy were nonresolving orbital disease with inadequate response to corticosteroids (44.4%) or a high suspicion of malignancy because of known pre-existing systemic malignancy or the presence of an atypical orbital mass in addition to enlarged muscles (44.4%). The histopathologic findings that suggested a diagnosis of IOM were splaying of muscle fibers by inflammatory infiltrates (n = 9) and mild fibrosis (n = 8) in the endomysium or replacing muscle fibers, with no granulomas or vasculitis. The inflammatory infiltrates identified were of chronic inflammatory cells, consisting of lymphocytes (n = 9), plasma cells (n = 6), and histiocytes (n = 6). Other less commonly identified cells were eosinophils (n = 4), polymorphonuclears (n = 1), and giant cells (n = 1). Muscle fiber degeneration or regeneration was evident in 5 patients. Four patients from the initial cohort showed inconclusive histologic findings on revision and were reassigned as suspected IOM. Conclusions The histopathologic features of involved muscles in IOM resemble those seen in idiopathic orbital inflammation and differ from those seen in common differential diagnoses. Extraocular muscle biopsy should be strongly considered whenever the presentation of orbital myositis is not typical or when significant underlying conditions are a possibility.

AimsTo review the distribution of pathology in extraocular muscle (EOM) biopsies performed at a tertiary orbital centre, identify clinical and imaging features which are associated with benign or malignant diseases and indicate when biopsy is necessary for EOM enlargement.MethodsRetrospective case series including 93 patients with EOM enlargement who underwent an EOM biopsy. Clinical, radiological and histopathological information was recorded from the medical records. Statistical analysis was used to compare variables between patients with malignant and benign biopsies.ResultsThe median age of subjects was 61.1 years. Forty-eight cases (52%) were benign and 45 (48%) were malignant. Those with malignant pathology were significantly older (PConclusionsBiopsy is warranted in those with an atypical presentation of EOM enlargement or suspected of having a malignancy. Some features such as age, gender, pain, diplopia, history of malignancy and eyelid erythema may help indicate a particular diagnosis; however, clinical features and imaging findings are often not pathognomonic of each disease.

PURPOSE: To describe the clinicopathological features and report the outcomes of treatment in lymphoma involving the extraocular muscles (EOM), the largest reported case-series. METHODS: A retrospective case series of patients with lymphoma involving the EOM from a single tertiary referral orbital center, between March 1992 and March 2018. Patients with other histopathologic diagnoses or who did not have an EOM biopsy were excluded. The main outcome measures were histologic evaluation and clinical follow-up including tumor response, recurrence, and survival. RESULTS: Twenty-five patients were included, 16 female; 9 male; median age 64.7 years (range 33.8-92.6 years). Unilateral involvement was present in 23 cases (92%). Lymphoma was found to be primary in 15 patients (60%), and any EOM could be affected by disease. Fourteen patients (56%) displayed impaired duction in the direction of the affected muscle. The commonest histologic type was extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue in 16 cases (64%) followed by follicular lymphoma in 3 cases (12%), diffuse large B-cell lymphoma in 2 cases (8%), gamma delta T-cell lymphoma in 2 cases (8%), small lymphocytic lymphom and lymphoplasmacytic lymphoma in 1 case each (4%). All 4 patients with high-grade lymphomas (diffuse large B-cell or T cell lymphoma) were found to have systemic disease. Patients were treated with combinations of radiotherapy, chemotherapy, or immunotherapy, with low toxicity. Two patients developed treatment-related complications. With a median follow-up of 26 months (range 3-108 months), there was only 1 recurrence, which was successfully salvaged with Rituximab, and no deaths due to lymphoma. CONCLUSIONS: Lymphoma of the EOM is a rare tumor with good response to treatment, few treatment-related complications and low risk of recurrence or mortality.A retrospective review of 25 patients with lymphoma of the extraocular muscles demonstrates excellent prognosis with a high rate of local remission (96%), 2 treatment-related complications, one recurrence, and no disease-related deaths.

A 68-year-old female presented for assessment of a space occupying lesion of her right orbit, demonstrated on MRI. An upper lid crease anterior orbitotomy was performed and the lesion excised completely. Postoperatively, she had reduced sensation in the distribution of the supraorbital nerve. Histopathologic examination of the excised lesion revealed a hybrid neurofibroma/schwannoma. This represents the fourth reported case of such a lesion arising within the orbit.

Purpose To investigate and characterize the clinical features of subtype-specific orbital lymphoma. Design Retrospective, interventional case series. Methods The study included 7 international eye cancer centers. Patient data were collected from January 1, 1980 through December 31, 2017. A total of 797 patients with a histologically verified orbital lymphoma were included. The primary endpoints were overall survival, disease-specific survival, and progression-free survival. Results The median age was 64 years, and 51% of patients (n = 407) were male. The majority of lymphomas were of B-cell origin (98%, n = 779). Extranodal marginal zone B-cell lymphoma (EMZL) was the most frequent subtype (57%, n = 452), followed by diffuse large B-cell lymphoma (DLBCL) (15%, n = 118), follicular lymphoma (FL) (11%, n = 91), and mantle cell lymphoma (MCL) (8%, n = 66). Localized Ann Arbor stage IE EMZL and FL were frequently treated with external beam radiation therapy. DLBCL, MCL, and disseminated EMZL and FL were primarily treated with chemotherapy. EMZL and FL patients had a markedly better prognosis (10-year disease-specific survival of 92% and 71%, respectively) than DLBCL and MCL patients (10-year disease-specific survival of 41% and 32%, respectively). Conclusions Four lymphoma subtypes were primarily found in patients with orbital lymphoma: EMZL, DLBCL, FL, and MCL. The histologic subtype was found to be the main predictor for outcome, with EMZL and FL patients having a markedly better prognosis than DLBCL and MCL.

The increasing use of methotrexate (MTX) and the newer biological agents in autoimmune disorders, particularly rheumatoid arthritis and dermatomyositis, has led to an increased incidence of non-Hod...

Incidental cases of localized fibrin-associated Epstein-Barr virus (EBV)+ large B-cell proliferations have been described at unusual anatomic sites and have been included in the category of diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) in the WHO Classification. We describe 12 cases and review the literature to define their clinicopathologic spectrum and compare features with typical cases of DLBCL-CI. Median age was 55.5 years with a M:F ratio of 3. In all 12 cases, the lymphoma was an incidental microscopic finding involving atrial myxomas (n=3), thrombi associated with endovascular grafts (n=3), chronic hematomas (n=2), and pseudocysts (n=4). All cases tested were nongerminal center B-cell origin, type III EBV latency, and were negative for MYC rearrangements and alternative lengthening of telomeres by FISH. Most showed high CD30, Ki67, and PD-L1, and low to moderate MYC and p53 expression. Among 11 patients with detailed follow-up, 6 were treated surgically, 3 with cardiac or vascular lesions had persistent/recurrent disease at intravascular sites, and 4 died of causes not directly attributable to lymphoma. Reports of previously published fibrin-associated cases showed similar features, whereas traditional DLBCL-CI cases with a mass lesion had significantly higher lymphoma-associated mortality. Fibrin-associated EBV+ large B-cell lymphoma is clinicopathologically distinct from DLBCL-CI, warranting separate classification. Most cases, particularly those associated with pseudocysts, behave indolently with the potential for cure by surgery alone and may represent a form of EBV+ lymphoproliferative disease rather than lymphoma. However, primary cardiac or vascular disease may have a higher risk of recurrence despite systemic chemotherapy.

Idiopathic sclerosing orbital inflammation (ISOI) is a rare and distinct clinicopathologic entity,1 which follows a recalcitrant clinical course, resulting in significant ocular morbidity. It is ch...

Introduction: An 80-year-old man had a 40-year history of chronic sensory ataxic neuropathy and 11 years of relapsing/remitting episodes of rapid deterioration with perioral paresthesiae and weakness of bulbar, respiratory, and limb muscles. Methods: An immunoglobulin M (IgM) paraprotein was detected 12 years before death, and Waldenstrom macroglobulinemia was diagnosed on bone marrow biopsy 3 years before death. Chronic ataxic neuropathy with ophthalmoplegia, IgM paraprotein, cold agglutinins, and anti-disialyl antibodies (CANOMAD) was diagnosed. Results: Comprehensive autopsy showed severe dorsal column atrophy and dorsal root ganglionopathy. A different pathology was identified in cranial and peripheral nerves, dorsal roots, and cauda equina, comprising infiltration of clonal B-lymphocytes within the endoneurium, perineurium, and leptomeninges. Conclusions: The autopsy provides evidence of the pathogenesis of the relapsing remitting component of CANOMAD, and we postulate that this may relate to the presence of clonal IgM anti-disiayl gangliosides secreting B-lymphocytes within nerves. Muscle Nerve 48: 599–603, 2013

Purpose To document subtype-specific clinical features of lymphoma of the eyelid, and their effect on patient outcome. Design Retrospective observational case series. Methods Patient data were collected from 7 international eye cancer centers from January 1, 1980 through December 31, 2015. The cases included primary and secondary lymphomas affecting the eyelid. Overall survival, disease-specific survival (DSS), and progression-free survival were the primary endpoints. Results Eighty-six patients were included. Mean age was 63 years and 47 (55%) were male. Non-Hodgkin B-cell lymphomas constituted 83% (n = 71) and T-cell lymphomas constituted 17% (n = 15). The most common subtypes were extranodal marginal-zone lymphoma (EMZL) (37% [n = 32]), follicular lymphoma (FL) (23% [n = 20]), diffuse large B-cell lymphoma (DLBCL) (10% [n = 9]), mantle cell lymphoma (MCL) (8% [n = 7]), and mycosis fungoides (MF) (9% [n = 8]). EMZL had a female predilection (69% [22 of 32]), whereas MCL (71% [5 of 7]) and MF (88% [7 of 8]) had a male predominance. MCL (57% [4 of 7]), DLBCL (56% [5 of 9]), and MF (88% [7 of 8]) were frequently secondary lymphomas. Localized EMZL and FL were mostly treated with external beam radiation therapy, whereas DLBCL, MCL, and high Ann Arbor stage EMZL and FL were frequently treated with chemotherapy. DLBCL and MCL had a poor prognosis (5-year DSS, 21% and 50%, respectively), whereas EMZL, FL, and MF had a good prognosis (5-year DSS, 88%, 88% and 86%, respectively). Conclusions Lymphoma of the eyelid consists mainly of the lymphoma subtypes EMZL, FL, DLBCL, MCL, and MF. High-grade DLBCL and MCL, as well as MF, are frequently secondary eyelid lymphomas. The main predictor of outcome was the histologic subtype: EMZL, FL, and MF had a significantly better prognosis than MCL and DLBCL.

Purpose: To compare and contrast the clinical, radiologic, pathologic, and genetic features of patients with ocular adnexal IgG4-related disease (IgG4-RD) and patients with adult ocular adnexal xanthogranulomatous disease (XG). Methods: This retrospective review study identified patients with histological evidence of either disease from records of the pathology department of our hospital from 1996 to 2014. Clinical, imaging, and a variety of histopathologic features were collected for 23 patients with IgG4-RD and 13 patients with XG. Next generation sequencing with a 50-gene cancer screening panel was performed on biopsy tissues from 10 patients in each group. Results: Statistical differences between the 2 groups include eyelid (67%; p = 0.0002) and anterior orbital (75%; p = 0.0352) predilection for XG except for Erdheim-Chester disease subgroup which was more posterior and diffuse. Eyelid involvement was rare (4%) for IgG4-RD. Involvement of orbital nerves was seen in 30% of IgG4-RD and 0% in XG (p = 0.0695). Five patients with IgG4-RD developed malignancy (4 lymphoma, 1 leiomyosarcoma), but none of XG patients. Discriminating pathological features were the presence of any IgG4+ plasma cells (p = 0.0121) and the ratio of IgG4+/IgG+ plasma cells (p =0.0294) for IgG4-RD. Five of 12 (42%) patients with XG had sufficient numbers of IgG4+ plasma cells/high power field to fulfill published diagnostic criteria for IgG4-RD, and 5 (42%) had a ratio of IgG4+/IgG+ plasma cells over 40%, but the numbers overall were less than seen in the IgG4-RD patients. The only genetic difference between the 2 groups was that BRAF V600E mutation was found in 1 of the 2 Erdheim-Chester disease patients, which form a subgroup of XG. Conclusions: IgG4-RD and XG share clinical, imaging, and histopathological features including IgG4+ plasma cells. Significant differences were the eyelid involvement in XG, orbital nerve involvement, and an elevated IgG4+/IgG+ ratio in IgG4-RD and the only genetic abnormality found was BRAF V600E mutation in the Erdheim-Chester disease subgroup of XG.

McKelvie P A, Thompson P A & Tam C S (2012) Histopathology 61, 212–233 Peripheral T cell and natural killer (NK) T cell lymphomas: a clinicopathological study from a single Australian centre Aims: Using pathological and clinical review, to identify all cases diagnosed as peripheral T cell and natural killer (NK) T cell lymphoma over 10 years from one metropolitan Australian hospital. Methods and results: Subtyping was performed using World Health Organization (WHO) 2008 criteria and a comprehensive immunohistochemical panel. Clinical data including follow-up were obtained. There were 47 cases, including 11 peripheral T cell lymphomas, not otherwise specified (NOS), nine extranodal NK T cell lymphomas, nasal type (eight nasal), eight primary cutaneous anaplastic large cell lymphomas, seven angioimmunoblastic T cell lymphomas, three anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphomas, four ALK-negative anaplastic large cell lymphomas, three enteropathic T cell lymphomas and two subcutaneous panniculitis-like T cell lymphomas. Follow-up of 46 of 47 cases (median time 45 months) revealed that 50% (23 of 46) of patients died. Five-year survival rates were: peripheral T cell lymphoma, NOS 39%; angioimmunoblastic T cell, 43%; nasal NK T 67%; ALK-negative anaplastic large cell lymphoma 67% (at 2 years); ALK+ anaplastic large cell lymphoma 33%; subcutaneous panniculitis-like T cell lymphomas 100%; primary cutaneous anaplastic large cell lymphoma 86%; and enteropathic T cell lymphoma 33% (at 1 year). One patient with Lennert lymphoma suffered four late cutaneous relapses. Conclusions: This first Australian clinicopathological series of peripheral T cell and NK T cell lymphoma shows epidemiological and survival data similar to those for Europe and North America.

We report an illustrative case of a 74-year-old man who, in the absence of intercurrent illness, presented with rapid cognitive decline. MRI showed bilateral, symmetrical, high T2-weighted signal in the anterior basal ganglia and medial thalami, extending to the periaqueductal grey matter, basal ganglia and basal frontal lobes. A (18)F-fluorodeoxyglucose-positron emission tomography scan showed widespread reduction of metabolism in the cortex of the frontal, temporal and parietal lobes, posterior cingulate gyrus, precuneus and caudate nuclei, with sparing of the sensorimotor cortex, thalami and lentiform nuclei. A mild vitamin B12 deficiency was found and despite normal thiamine levels, intravenous (IV) thiamine and vitamin B therapy was commenced, with a short course of IV methylprednisolone and tetracycline. Repeat neuropsychological assessment four weeks following treatment revealed increased alertness and interactiveness but significant cognitive decline persisted. Unexpectedly, the patient suffered a transmural anterior myocardial infarction six weeks after presentation and died within 24hours. An a autopsy showed: global reduction in cytochrome oxidase (COX) activity in all skeletal muscles examined; bilateral, symmetrical, hypervascular, focally necrotizing lesions in the substantia nigra, periaqueductal grey matter, superior colliculi, medial thalami anteriorly and posteriorly, as well as in the putamena but the mammillary bodies were not affected. Biochemical analysis of fresh muscle confirmed selective deficiency of complex IV of the oxidative phosphorylation chain. A diagnosis of late-adult onset Leigh syndrome was made. Multiple genetic studies failed to identify the specific underlying mutation. The relevant literature is reviewed.

A case of painless isolated extraocular muscle sarcoid and a literature review are presented. The atypical features in our case include a lack of overt inflammatory symptoms and signs, such as pain, ptosis, and diplopia. The presentation of minimal symptoms without improvement warrant a biopsy to establish the diagnosis and to administer appropriate treatment in order to prevent potential long-term complications from sarcoidosis.

Introduction: Orbicularis oculi (OO) muscle has recently proposed as a suitable muscle for biopsy to diagnose mitochondrial cyopathy: Methods: Enzyme histochemical and immunohistochemical studies were performed on OO muscle obtained from 18 patients aged 37–87 years (median 64 years), 6 males, 12 females, who were undergoing routine upper blepharoplasty surgery. Results: We confirmed the marked type II fibre (fast myosin heavy chain) predominance (89%) but also noted a different proportion and distribution of mitochondria in these fibres with occasional pseudo-‘ragged-red’ fibres with prominent subsarcolemmal and cytoplasmic aggregation of mitochondria. Cytochrome oxidase-negative fibres and true ‘ragged-red’ fibres were found at all ages over 40 years at levels that approach those used for diagnosis of mitochondrial cytopathy in peripheral or limb skeletal muscles. Conclusion: We would therefore urge caution in the use of OO as muscle biopsy for diagnosis of mitochondrial cytopathy and advise concomitant biopsy of limb skeletal muscle and/or supplementary genetic studies.

Epidermolysis bullosa associated with muscular dystrophy is a rare, autosomal recessive form of epidermolysis bullosa simplex caused by mutations in the plectin gene, PLEC1. We describe a phenotypically mild case due to compound heterozygous mutations in PLEC1 (2677_2685del and the novel mutation Q1644X). Clinical features included mild skin blistering since birth, slowly progressive and late-onset upper limb-predominant weakness, facial weakness, ptosis, incomplete ophthalmoplegia, and paroxysmal atrial fibrillation.

Temporal lobe epilepsy is the commonest partial epilepsy of adulthood. Although generally perceived as an acquired disorder, several forms of familial temporal lobe epilepsy, with mesial or lateral seizure semiology, have been described. Descriptions of familial mesial temporal lobe epilepsy have varied widely from a benign epilepsy syndrome with prominent déjà vu and without antecedent febrile seizures or magnetic resonance imaging abnormalities, to heterogeneous, but generally more refractory epilepsies, often with a history of febrile seizures and with frequent hippocampal atrophy and high T₂ signal on magnetic resonance imaging. Compelling evidence of a genetic aetiology (rather than chance aggregation) in familial mesial temporal lobe epilepsy has come from twin studies. Dominant inheritance has been reported in two large families, though the usual mode of inheritance is not known. Here, we describe clinical and neurophysiological features of 20 new mesial temporal lobe epilepsy families including 51 affected individuals. The epilepsies in these families were generally benign, and febrile seizure history was infrequent (9.8%). No evidence of hippocampal sclerosis or dysplasia was present on brain imaging. A single individual underwent anterior temporal lobectomy, with subsequent seizure freedom and histopathological evidence of hippocampal sclerosis was not found. Inheritance patterns in probands' relatives were analysed in these families, together with 19 other temporal lobe epilepsy families previously reported by us. Observed frequencies of epilepsies in relatives were lower than predicted by dominant Mendelian models, while only a minority (8/39) of families could be compatible with recessive inheritance. These findings strongly suggest that complex inheritance, similar to that widely accepted in the idiopathic generalized epilepsies, is the usual mode of inheritance in familial mesial temporal lobe epilepsy. This disorder, which appears to be relatively common, and not typically associated with hippocampal sclerosis, is an appropriate target for contemporary approaches to complex disorders such as genome-wide association studies for common genetic variants or deep sequencing for rare variants.

Ocular adnexal lymphomas comprise 1% to 2% of all non-Hodgkin lymphomas and about 8% of extranodal lymphomas. They are a heterogeneous group of malignancies, the majority of which are primary extranodal lymphoma with most (up to 80%) of the marginal zone of mucosa associated lymphoid tissue type (MALT lymphoma). This review will encompass the incidence, histology, immunophenotyping, recent advances in molecular and cytogenetics, clinical features including outcome, and prognostic factors. The association with Chlamydia psittaci and the very recently recognized occurrence in the context of IgG4-related sclerosing disease will be discussed. Finally, traditional (surgery, radiotherapy, chemotherapy) and newer forms of therapy (immunotherapy and radioimmunotherapy) will be reviewed.

Aims Extranodal NK/T cell lymphoma, nasal type (ENKTCL) is usually composed of medium- to large-sized lymphoid cells showing prominent angiotrophism and tumour cell necrosis. We report 13 cases composed predominantly of small lymphocytes diagnosed in the United States and Western Europe. Methods and results Patients included seven females and six males aged 17–75 years. Ten presented with sinonasal and three with buccal disease. Nine had stage IE/IIE and four had stage IV disease. In five of seven patients with multiple biopsies at different time-intervals, the lymphoma was misinterpreted as representing chronic inflammation on an earlier biopsy. In all cases morphology showed a dense infiltrate of small lymphoid cells with minimal cytological atypia. Necrosis, angioinvasion and angiodestruction were each seen in 17%, 22% and 17% of biopsies. Median Ki67 was 5%. Four patients died of lymphoma 4–16 months after diagnosis, including three of four patients with stage IV disease; seven (54%) are alive with no evidence of disease at a median of 39 months; one patient with stage IV disease is alive at 10 months and one recurred at 17 months. Conclusions In sinonasal biopsies with predominantly small lymphocytic infiltrates with admixed chronic inflammation, focal hypercellularity, focal surface ulceration or microscopic bone invasion by small lymphoid cells should alert pathologists to the possibility of small-cell predominant ENKTCL. Awareness of the full histological spectrum of ENKTCL, particularly in non-endemic areas, is important in avoiding a delay in diagnosis and ensuring timely initiation of therapy.

Three women (aged 21–36 years) developed acute illnesses that were similar to epidemic encephalitis lethargica. Each presented with a neuropsychiatric disturbance that was succeeded by pyrexia, a fluctuating conscious state and involuntary movements including oculogyria. Cerebrospinal fluid examination showed a predominantly lymphocytic pleocytosis (64–120 × 10 6 cells/L) and oligoclonal bands were detected in two cases. Two patients died, while the third made a gradual recovery. Post-mortem examination in the two fatal cases showed changes of lymphocytic meningitis and focal diencephalic lymphocytic infiltration, although these changes were mild relative to the effects of the clinical illness. The diagnosis of sporadic encephalitis lethargica relies on identifying shared clinical features with the past epidemic disease plus circumstantial evidence of immunological activity from laboratory investigations and some tests of exclusion of other disorders.

Cyclophosphamide is a potent cytotoxic agent used in many clinical settings. The main risks of cyclophosphamide therapy include hematological disorders, infertility, hemorrhagic cystitis and malignancies. Gastrointestinal side effects reported to date are often non-specific and not severe. We present the first case of a fatal small bowel enteritis and pan-colitis which appears to be associated with cyclophosphamide. We aim to raise the readers' awareness of this significant adverse event to facilitate clinical suspicion and early recognition in potential future cases.

Primary signet ring cell carcinoma of the eyelid (PSCE) is a very rare tumour. Only a few cases having been reported to date. The majority of patients have been middle-age to elderly men. Different treatment modalities have been applied in cases of PSCE. Here, we report a case of PSCE in a man treated with orbital exenteration and radiotherapy.

Impression cytology, either using cellulose acetate strips or the Biopore membrane device, is a simple, noninvasive technique that aids in the diagnosis of several disorders of the ocular surface. These disorders include ocular surface squamous neoplasia, dry eye syndrome, limbal stem-cell deficiency, specific viral infections, vitamin A deficiency, allergic disorders, conjunctival melanosis, and malignant melanoma. Another advantage is the preservation of limbal stem cells, which occur in the basal layer of the limbal epithelium and are responsible for renewal of the corneal epithelium. The Biopore membrane device is particularly user friendly, with little expertise required and adequate specimens obtained in a very high percentage of cases. The most common applications in diagnostic ocular pathology are:(i) primary diagnosis and follow-up of ocular surface squamous neoplasia, including after therapy with topical mitomycin C. The sensitivity is high (78-87%); and (ii) dry eye syndrome where squamous metaplasia and/ or hyperkeratosis are noted. Certain limitations of the technique for diagnosis of squamous neoplasia include the fact that dysplasias are often keratinizing and may yield very few or even no dysplastic cells with impression cytology. Secondly, no definite cytologic criteria reliably distinguish invasive SCC of ocular surface from in situ disease. Other applications include the rapid specific diagnosis of ocular surface infections with herpes simplex, adeno-, and varicella zoster viruses. Impression cytology samples may also be used to obtain mRNA, cells for phenotyping by flow cytometry, and proteins for Western blotting for research studies.

Objective To examine the clinical profile of patients with myotoxicity due to HMG-CoA reductase inhibitors and the pathological features in the biopsies. Design All patients receiving HMG-CoA reductase inhibitors who underwent muscle biopsy at the State Neuropathology Service, Melbourne, from October 2000 to September 2001 were identified, and clinical questionnaires were completed by the referring doctor. Results Ten patients, including 4 males and 6 females, aged 50 to 76 years (median, 69.5 y), were identified. Six patients were diabetic and one was severely hypothyroid. Statins included simvastatin in 5, atorvastatin in 4, and cerivastatin in 1. Six patients had either a recent doubling in dosage of statin or change to another statin. Six patients were also taking one or more drugs with known interaction with HMG-CoA reductase inhibitors (gemfibrozil, ketoconazole, calcium channel antagonists, dothiepin, celecoxib, amiodarone). All patients had weakness, 8 had myalgias, and 3 had myoglobinuria. Peak creatine kinase (CK) elevation ranged from 1100 to 160,000 U/L (median, 16,000 U/L). Following cessation of statins, resolution of symptoms and normalization of CK levels were noted in all within a few months. All muscle biopsies showed necrotizing myopathy with minimal inflammation in 4 (40%). Histochemical studies did not suggest mitochondrial cytopathy. Conclusion Myotoxicity due to HMG-CoA reductase inhibitors commonly occurs in patients taking concomitant medication known to interact with metabolism of these agents, such as gemfibrozil or ketoconazole, or with an increase in dose. In addition, elderly patients with obesity, diabetes mellitus, and hypothyroidism appear to be at increased risk of developing myotoxicity.

Aim: To retrospectively study 26 patients with squamous cell carcinoma (SCC) of the ocular surface to determine pathological and clinical characteristics of tumour associated with outcome. Methods: Patients with conjunctival SCC from St Vincent9s Hospital and the private ophthalmology practices of the authors were reviewed. Results: Patents were usually male (77%), elderly (69% > 60 years of age), with most lesions (81%) occurring at the limbus. Seven patients (27%) suffered recurrent ocular surface squamous neoplasia (OSSN) within 4–15 months and two of these patients (8%) died of metastatic disease. Intraocular invasion was noted in three patients (11%), while corneal and/or scleral invasion was found in eight (30%). Orbital invasion was noted in four patients (15%). Six required orbital exenteration. Preoperative impression cytology of five patients with minimally invasive disease showed OSSN in four (80%). In situ carcinoma could not be differentiated from minimally invasive disease using impression cytology. Preoperative diagnosis of SCC was made in 35% of cases. Clinical accuracy was higher for larger lesions (>10 mm) and those with hyperkeratosis. Conclusions: Conjunctival SCC occurs in sun damaged ocular surface, usually at the limbus in elderly men. Recurrence of OSSN is common with significantly increased risk for older patients, lesions of large diameter, high proliferation index (Ki-67 score), and positive surgical margins. Orbital exenteration may be required for control of local disease and death from metastatic disease occurs in a small percentage of patients.

Summary Multiple pituitary adenomas may occur in up to 1.6–3.3% of patients with Cushing’s syndrome. We report three patients with double pituitary adenomas detected at surgery. Two patients had Cushing’s disease, but trans-sphenoidal exploration revealed a small prolactinoma in each. One prolactinoma also contained small numbers of basophils. Reoperation in both patients because of persistent Cushing’s syndrome showed an ACTH-secreting micro-adenoma. The third patient with acromegaly had two macro-adenomas discovered in different parts of the gland at surgery: one plurihormonal and one null cell tumour. Careful evaluation of pre-operative MRI may not always detect more than one pituitary adenoma.

Background: This study involved 73 patients with lymphoproliferative lesions of the ocular adnexa. The lesions were categorized using the Revised European American Lymphoma classification of lymphoid tissues and analysed to determine the frequency and prognostic impact of tumour type, location, stage and patient's age and sex. Methods: The clinical, histopathological, immunohistochemical and phenotypic analysis by flow cytometry and follow-up data were studied. Results: The ocular adnexal lymphoproliferative lesions included 70 lymphomas and six reactive lymphoid hyperplasia. Seventy-nine per cent had stage IE disease, 4% stage II, 1.5% stage III and 15.5% stage IV. Five patients (7%) had a past history of systemic lymphoma. Major histological types were extranodal marginal zone lymphoma (MZL) in 44 (63%), follicular (FL) in 12 (17%), diffuse large B-cell (DLBCL) in eight (11%), mantle cell (MCL) in two (3%), B-cell chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma in two (3%), peripheral T-cell lymphoma (PTCL) one (1.5%) and natural killer cell lymphoma (NKCL) in one (1.5%). Longest survival was seen in those with low-grade lymphomas (MZL and FL) and worst in PTCL and NKCL. Lymphoma-related mortality was 2% for MZL, 33% for FL, 38% for DLBCL, and 100% for MCL, PTCL and NKCL. Systemic lymphoma was present prior to, at presentation or at subsequent follow up in 26/68 (39%) of all lymphoma patients, 17% for MZL, 38% for DLBCL, 83% for FL, and 100% for MCL, CLL, PTCL and NKCL. Conclusion: The majority of ocular adnexal lymphomas were low-grade B-cell lymphomas (MZL). Multivariate analysis showed that the only significant independent predictors of all causes of mortality were the histological type of lymphoma and the stage of disease at presentation.

A 73-year-old woman developed multiple depigmented lesions in the fundus 4-6 months after an episode of acute Herpes zoster ophthalmicus. Post-mortem examination of the globe 15 years after this acute episode confirmed multiple old chorioretinal scars probably due to vasculitis of the short posterior ciliary arteries and branches. Patchy old infarcts were also noted in the iris.

We present a 40-year-old man with conus medullaris syndrome secondary to a cystic lesion of the ventriculus terminalis (CLVT) and review the relevant literature. The patient presented with 4 years of worsening right leg weakness, and examination showed bilateral fasciculations and hyporeflexia. MRI showed a cystic lesion at T11-12. He was managed with a T11-12 laminectomy and fenestration of an intramedullary cyst. A total of 32 patients, including ours, have been described since 1968: 24 were female with a mean age of 46.6 years. All patients presented symptomatically: five were managed conservatively, four using percutaneous aspiration under MRI guidance, and 22 with open surgery. We conclude that symptomatic patients are best managed surgically, although percutaneous aspiration is an emerging technique.

Purpose: To report on the rapid and sustained effect following injection of intravitreal methotrexate (IVTMTX) in intraocular T-cell lymphoma.Design: Report of 2 cases.Methods: A young male with natural killer/T-cell lymphoma presented with infiltrative nodular iridocyclitis and received a single IVTMTX. An elderly female with peripheral T-cell lymphoma presented with a hypopyon, infiltrative iridocyclitis, and choroidal effusions and received 3 IVTMTX over 4 months.Results: Both patients responded well after the first injection, with resolution of signs within 1 week and improvement in vision.Conclusions: IVTMTX may be effective as a palliative, vision-restoring measure in patients with systemic T-cell lymphoma.

PURPOSE: To report bilateral epibulbar xanthomatous lesions in an adult with a normal serum lipid profile and no cutaneous or systemic features of a histiocytic disease. METHODS: Clinicopathologic report. RESULTS: A 44-year-old man presented with gradually enlarging yellow epibulbar masses in both eyes. The lesions had recurred after excisions performed 2 years previously. Systemic evaluation was normal. Excisional biopsies were performed, and histological examination revealed numerous foamy histiocytes with scattered Touton giant cells and lymphocytes. No recurrence was observed after 1 year of follow-up. CONCLUSION: Xanthomatous epibulbar lesions are exceedingly rare and may occur as an isolated finding. Evaluation should be directed toward detecting underlying non-Langerhans cell histiocytic diseases and disorders of lipid metabolism. Recurrent lesions may be successfully treated by surgical excision.

Orbital Langerhans cell histiocytosis (LCH) without bone involvement is rare. Isolated involvement of an extraocular muscle without bone change, to the best of the authors' knowledge, has not been previously reported. They describe a unique case of unifocal LCH of the superior oblique muscle with no bone involvement. A 16-year-old girl presented with a 2-week history of diplopia and headache. CT and MRI showed an enlarged right superior oblique muscle with no associated bone involvement. Biopsy with partial debulking revealed LCH and staging confirmed unifocal disease. The lesion underwent complete radiologic resolution following surgery. There was no recurrence after 16 months follow up.