Malee Fernando

Vascular pathologies and cognition in a population-based cohort of elderly people.

The MRC Cognitive Function and Ageing Study (CFAS) is a prospective longitudinal study of a population-based cohort of elderly people in six UK sites, evaluated using psychometric instruments and questionnaires to elucidate physical and mental health. Data from the core study includes prevalence and incidence rates for dementia and longitudinal measures of cognitive decline together with data on genetic risk factors for dementia. A neuropathology study runs in collaboration with the core study based on premortem counselling of individual respondents or carers. Analysis of pathological data from the first 209 accumulated brain donations showed that both Alzheimer-type pathologies (ATP) and vascular pathologies (including congophilic amyloid angiopathy (CAA)) were common in both demented and non-demented respondents. Although many cases fulfil conventional diagnostic criteria for the pathological diagnosis of Alzheimer disease, the data differ from those published from conventional studies of hospital or memory clinic cohorts. In particular, there are individuals whose total burden of pathology is inappropriately high or low compared with their clinical dementia status, even when all pathologies are considered in a multivariable model of dementia risk factors (25% of respondents misdiagnosed from pathology findings). Vascular pathology is so common that few dementia cases lack a mixed component of both ATP and vascular lesions (pure AD cases, 21%). More recently, the study has examined white matter pathology in this cohort as a potential manifestation of small-vessel disease (SVD) in the ageing brain. Using an MRI strategy to image formalin-fixed brain slices, the study shows that white matter lesions (WMLs) are common (94% overall frequency) and are an independent risk factor for dementia using multivariable analysis.

High Quality Genomic Copy Number Data from Archival Formalin-Fixed Paraffin-Embedded Leiomyosarcoma: Optimisation of Universal Linkage System Labelling

Most soft tissue sarcomas are characterized by genetic instability and frequent genomic copy number aberrations that are not subtype-specific. Oligonucleotide microarray-based Comparative Genomic Hybridisation (array CGH) is an important technique used to map genome-wide copy number aberrations, but the traditional requirement for high-quality DNA typically obtained from fresh tissue has limited its use in sarcomas. Although large archives of Formalin-fixed Paraffin-embedded (FFPE) tumour samples are available for research, the degradative effects of formalin on DNA from these tissues has made labelling and analysis by array CGH technically challenging. The Universal Linkage System (ULS) may be used for a one-step chemical labelling of such degraded DNA. We have optimised the ULS labelling protocol to perform aCGH on archived FFPE leiomyosarcoma tissues using the 180k Agilent platform. Preservation age of samples ranged from a few months to seventeen years and the DNA showed a wide range of degradation (when visualised on agarose gels). Consistently high DNA labelling efficiency and low microarray probe-to-probe variation (as measured by the derivative log ratio spread) was seen. Comparison of paired fresh and FFPE samples from identical tumours showed good correlation of CNAs detected. Furthermore, the ability to macro-dissect FFPE samples permitted the detection of CNAs that were masked in fresh tissue. Aberrations were visually confirmed using Fluorescence in situ Hybridisation. These results suggest that archival FFPE tissue, with its relative abundance and attendant clinical data may be used for effective mapping for genomic copy number aberrations in such rare tumours as leiomyosarcoma and potentially unravel clues to tumour origins, progression and ultimately, targeted treatment.

Establishment and molecular characterisation of seven novel soft-tissue sarcoma cell lines.

Background:Soft-tissue sarcomas (STS) are a diverse group of malignancies that remain a diagnostic and therapeutic challenge. Relatively few reliable cell lines currently exist. Rapidly developing technology for genomic profiling with emerging insights into candidate functional (driver) aberrations raises the need for more models for in vitro functional validation of molecular targets.Methods:Primary cell culture was performed on STS tumours utilising a differential attachment approach. Cell lines were characterised by morphology, immunocytochemistry, proliferation assays, short tandem repeat (STR) and microarray-based genomic copy number profiling.Results:Of 47 STS cases of various subtypes, half formed adherent monolayers. Seven formed self-immortalised cell lines, including three undifferentiated pleomorphic sarcomas, two dedifferentiated liposarcomas (one of which had received radiotherapy), a leiomyosarcoma and a myxofibrosarcoma. Two morphologically distinct yet genetically identical variants were established in separate cultures for the latter two tumours. All cell lines demonstrated genomic and phenotypic features that not only confirm their malignant characteristics but also confirm retention of DNA copy number aberrations present in their parent tumours that likely include drivers.Conclusions:These primary cell lines are much-needed additions to the number of reliable cell lines of STS with complex genomics available for initial functional validation of candidate molecular targets.

IgG4-related sclerosing disease clinically mimicking oral squamous cell carcinoma

IgG4-related sclerosing disease is a distinct clinicopathologic entity known to involve the maxillofacial region, particularly the salivary, lacrimal, and pituitary glands. We report a case with lesions involving the tongue and palatine tonsil with associated skin lesions. A 45-year-old female patient presented with a history of soreness, dysphagia, and an asymptomatic rash involving the upper trunk. The initial clinical diagnosis of her oral lesions was squamous cell carcinoma. The diagnosis of an IgG4-related lesion was confirmed by histologic examination of the oral and skin lesions as well as confirmation of raised serum IgG4 levels. Tapering systemic corticosteroid therapy resulted in complete resolution of the lesions. This is the first report of IgG4-related sclerosing disease presenting as concurrent oral and skin lesions, with the oral lesion clinically resembling oral squamous cell carcinoma. Such lesions present a diagnostic challenge, but the outcome is very favorable.

Non Healing Ulcer of the Breast Due to Calciphylaxis

A 68-year-old Asian woman presented with 2-week history of a painful left periareolar lump. Some of her medical history included: type II diabetes mellitus, chronic renal failure, moderate obesity, left chronic mastitis, mild hypercalcemia (2.60 mmol ⁄ L), and hypomagnesemia. Imaging and core biopsy of the breast diagnosed fat necrosis. The painful lump progressed into an ulcer over 4-month period. The second core biopsy of the breast lesion showed inflammatory changes only. Culture for Acid Fast Bacilli was negative while microscopy showed coliforms. The ulcer did not heal after several courses of antibiotics and wound dressing. Instead, it recurred and persisted for 7 months, progressing into necrosis. She underwent a vertical, central segmental wedge wide local excision with primary closure and satisfactory postoperative healing. The histology revealed extensive areas of ischemia, which were associated with abnormal small and medium size blood vessels (Fig. 1). The main abnormality of the blood vessel wall was calcification of the media (Fig. 2) with obliteration ⁄ hypertrophy of the intima and narrowing of the vessel lumen (Fig. 3). One of the vessels was completely occluded by thrombus (Fig. 4). In view of these findings, diagnosis of calciphylaxis in the breast was made, and previous biopsies were reviewed. These biopsies contained no blood vessels and suspicion of calciphylaxis could not have been raised earlier. Calciphylaxis occurring in the breast and resulting in chronic ulceration is uncommon. Only few cases have been reported in literature to date. It is characterized by calcification of small and medium sized vessels and is usually seen in patients with end stage chronic renal failure and secondary hyperparathyroidism. Our patient had normal parathyroid hormone level at time of presentation. Some cases have been reported in association with metastatic disease. The pathogenesis of calciphylaxis is not well understood

Enteropathy-associated T-cell lymphoma, lacking MHC class II, with immune-privileged site recurrence, presenting as bilateral ocular vitreous humour involvement – a case report

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Orbital Lipofibromatosis in a Child: A Case Report

Purpose: Lipofibromatosis is a rare, benign, soft tissue tumor that typically involves extremities particularly in children. We report a young girl with lipofibromatosis involving the superotemporal quadrant of the left orbit. Case Report: An 8-year-old girl presented with a history of a gradually expanding mass in the superotemporal quadrant of the left orbit over several years. Orbital imaging showed a soft tissue mass superolateral to the globe with possible infiltration into the lacrimal gland and lateral rectus muscle. The lesion was excised preserving adjacent structures. Histopathological examination revealed that the lesion consisted of adipose tissue with fibroblastic elements, being consistent with a diagnosis of lipofibromatosis. No recurrence of the lesion was seen in 18 months follow-up. Comment: Orbital involvement of lipofibromatosis as reported here is indeed a very rare entity. Diagnosis can be confirmed by histopathological analysis. As the lesion has a tendency to infiltrate into surrounding structures, surgical excision without hampering important structures is a treatment of choice.

Paraneoplastic granulomatous vitritis and retinitis as a presentation of recurrent classical Hodgkin’s lymphoma

We describe a unique case of a patient with an established diagnosis of Hodgkin’s lymphoma in clinical remission who later presented with apparent vitreous inflammation. A vitreous biopsy (including fortuitously some peripheral retinal fragments) exhibited granulomatous inflammation. Since the latter can be a paraneoplastic phenomenon of active Hodgkin’s lymphoma in distant organ sites, the haematologists were alerted to the possibility of recurrent lymphoma, despite the patient having no clinical symptoms. Repeat body imaging showed enlarged mediastinal lymph nodes, biopsy of which confirmed recurrent Hodgkin’s lymphoma. The patient responded well to systemic chemotherapy with resolution of the visual symptoms. This case report illustrates the importance of vitreous biopsy in this clinical setting and how to interpret the significance of granulomas in this context, and outlines a unique vitreo-retinal paraneoplastic granulomatous presentation in the setting of recurrent Hodgkin’s lymphoma and how this diagnosis triggered a prompt review of the patient who had no constitutional symptoms, with hopefully a favourable impact on prognosis given the early recurrent disease detection.

Metachronous Diffuse Large B-Cell Lymphoma and Kaposi Sarcoma of the Right Eyelid and Lacrimal Gland in a Patient with Granulomatous Common Variable Immunodeficiency

Purpose: To describe the ophthalmic and histopathological features of a female with granulomatous common variable immunodeficiency (CVID) who presented with upper-lid swelling. Procedures: The patient underwent a biopsy of the right upper lid/palpebral lacrimal gland with imaging showing a left-sided nasopharyngeal mass, multiple lymph nodes within the mediastinum, bilateral lung nodules and a peritoneal nodule in the right iliac fossa. The right upper-lid swelling progressed and was subject to a second biopsy. Results: The first right upper-lid biopsy revealed a diffuse large B-cell lymphoma (DLBCL), confirmed with clonal IgH gene rearrangement with PCR. The nasopharyngeal mass and lymph nodes were suspected clinically to be DLBCL. However, a biopsy of the nasopharyngeal mass showed Kaposi sarcoma (KS). The second biopsy of the right upper lid/palpebral lacrimal gland revealed KS with no evidence of DLBCL. Conclusion: This is the first documentation of periocular/orbital metachronous DLBCL and KS in a patient with granulomatous CVID. We discuss the role of fluctuating immunity in CVID to explain the spontaneous regression of the DLBCL and the varying clinical picture.

Conjunctival Angioimmunoblastic T-Cell Lymphoma

Angioimmunoblastic T-cell lymphoma (AITL) represents an uncommon variant of T-cell lymphomas and most often presents insidiously with systemic symptoms. This report constitutes the first documented case of conjunctival AITL, masquerading as nodular episcleritis, and describes both the clinical and pathological findings. Furthermore, conjunctival T-cell lymphoma in general remains a rare occurrence, and a survey of previously reported cases reveals a wide variation in clinical presentation. A high index of suspicion, thorough examination and conjunctival biopsy are essential to reaching the diagnosis of conjunctival lymphoma.