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Recurrent bilateral eyelid and conjunctival granulomatosis in Churg-Strauss syndrome

Jainuddin NF, Aliff IC, Chiew SF, Ramli N

Med J Malaysia, 2020 01;75(1):86-87.
PMID: 32008029

A 47-year-old woman with poorly controlled asthma and allergic rhinitis presented with recurrent episodes of bilateral upper eyelid swelling associated with forniceal conjunctival mass for the past 10 years. Routine blood investigations showed raised IgE levels and raised eosinophil counts. The diagnosis of Churg-Strauss syndrome (CSS) was made following biopsy of the conjunctival mass. The symptoms responded well to oral steroid treatment but recurred following cessation of the therapy. The patient was co-managed with a rheumatologist and the patient currently remains stable and is on oral Methotrexate and low dose oral steroids. Ocular involvement in CSS is unusual but this unique presentation of CSS was successfully managed, and the patient remains in remission.
Gastrointestinal stromal tumour in a jejunal diverticulum: The eighth reported case worldwide with a brief review of the literature

Chiew SF, Toh YF, Looi LM, Cheah PL

Malays J Pathol, 2023 Dec;45(3):473-478.
PMID: 38155388

Jejunal diverticulosis is uncommon and so are gastrointestinal stromal tumours (GIST) arising in the jejunum. GIST arising in a jejunal diverticulum is a rarity and to date there are only 7 cases in the English literature. Our case of GIST occurring in a jejunal diverticulum of a 48-year-old lady would be the first reported in Malaysia and the 8th in the world. As in most cases, the clinical presentation and radiological findings of this patient were non-specific. With a history of acute abdominal pain, vomiting and fever, the patient was provisionally diagnosed as a case of twisted ovarian cyst and subjected to laparotomy. An intact roundish jejunal diverticulum 5.0 cm x 5.0 cm, about 50 cm distal to the duodeno-jejunal junction was found and resected with a segment of small intestine. Microscopic examination showed a tumour of the cut open diverticular wall, with epithelioid to spindled cells, demonstrating a mitotic rate of 1-2 per 5 mm2, confined to, while infiltrating the wall of the diverticulum. The immunohistochemical profile of positive staining for CD117, DOG-1, smooth muscle actin and CD34, and negative expression of desmin and S100 protein, clinched the diagnosis of GIST. Based on the AFIP Criteria for risk stratification,1 the patient was categorised as having moderate risk for disease progression, and was not offered further targeted imatinib as an immediate measure. The patient has remained well at the time of writing i.e. 8 months following excision, and continues on active surveillance by the surgical and oncological teams, with the option of imatinib, should the necessity arise. This case is presented not merely for the sake of documenting its rarity, but as a reminder to stay alert for uncommon conditions in histopathology practice.
Fulltext Magnetic resonance imaging features of invasive breast cancer association with the tumour stromal ratio

Ab Mumin N, Ramli Hamid MT, Abdul Hamid S, Chiew SF, Ahmad Saman MS, Rahmat K

PLoS One, 2023;18(8):e0290772.
PMID: 37624821 DOI: 10.1371/journal.pone.0290772

OBJECTIVE: To assess the association between breast cancer tumour stroma and magnetic resonance imaging (MRI) features.
MATERIALS AND METHODS: A total of 84 patients with treatment-naïve invasive breast cancer were enrolled into this retrospective study. The tumour stroma ratio (TSR) was estimated from the amount of tumour stroma in the pathology specimen of the breast tumour. The MRI images of the patients were analysed based on Breast Imaging Reporting and Data Systems (ACR-BIRADS) for qualitative features which include T2- weighted, diffusion-weighted images (DWI) and dynamic contrast-enhanced (DCE) for kinetic features. The mean signal intensity (SI) of Short Tau Inversion Recovery (STIR), with the ratio of STIR of the lesion and pectoralis muscle (L/M ratio) and apparent diffusion coefficient (ADC) value, were measured for the quantitative features. Correlation tests were performed to assess the relationship between TSR and MRI features.
RESULTS: There was a significant correlation between the margin of mass, enhancement pattern, and STIR signal intensity of breast cancer and TSR. There were 54.76% (n = 46) in the low stromal group and 45.24% (n = 38) in the high stromal group. A significant association were seen between the margin of the mass and TSR (p = 0.034) between the L/M ratio (p <0.001), and between STIR SI of the lesion and TSR (p<0.001). The median L/M ratio was significantly higher in the high TSR group as compared to the lower TSR group (p < 0.001).
CONCLUSION: Breast cancer with high stroma had spiculated margins, lower STIR signal intensity, and a heterogeneous pattern of enhancement. Hence, in this preliminary study, certain MRI features showed a potential to predict TSR.
Fulltext Indication of high lipid content in epithelial-mesenchymal transitions of breast tissues

Sabtu SN, Sani SFA, Looi LM, Chiew SF, Pathmanathan D, Bradley DA, et al.

Sci Rep, 2021 Feb 05;11(1):3250.
PMID: 33547362 DOI: 10.1038/s41598-021-81426-x

The epithelial-mesenchymal transition (EMT) is a crucial process in cancer progression and metastasis. Study of metabolic changes during the EMT process is important in seeking to understand the biochemical changes associated with cancer progression, not least in scoping for therapeutic strategies aimed at targeting EMT. Due to the potential for high sensitivity and specificity, Raman spectroscopy was used here to study the metabolic changes associated with EMT in human breast cancer tissue. For Raman spectroscopy measurements, tissue from 23 patients were collected, comprising non-lesional, EMT and non-EMT formalin-fixed and paraffin embedded breast cancer samples. Analysis was made in the fingerprint Raman spectra region (600-1800 cm-1) best associated with cancer progression biochemical changes in lipid, protein and nucleic acids. The ANOVA test followed by the Tukey's multiple comparisons test were conducted to see if there existed differences between non-lesional, EMT and non-EMT breast tissue for Raman spectroscopy measurements. Results revealed that significant differences were evident in terms of intensity between the non-lesional and EMT samples, as well as the EMT and non-EMT samples. Multivariate analysis involving independent component analysis, Principal component analysis and non-negative least square were used to analyse the Raman spectra data. The results show significant differences between EMT and non-EMT cancers in lipid, protein, and nucleic acids. This study demonstrated the capability of Raman spectroscopy supported by multivariate analysis in analysing metabolic changes in EMT breast cancer tissue.
Epithelial-mesenchymal transition profiles in triple negative breast carcinoma may explain its aggressive nature

Chiew SF, Looi LM, Cheah PL, Teoh KH, Chang SW, Abdul Sani SF

Malays J Pathol, 2023 Dec;45(3):363-374.
PMID: 38155378

Epithelial-mesenchymal transition (EMT) is increasingly explored in cancer progression. Considering that triple negative (TN) breast cancer has the poorest survival among molecular subtypes, we investigated 49 TN, 45 luminal and 25 HER2-enriched female breast carcinomas for EMT expression (using E-cadherin and vimentin immunohistochemistry) against lymphovascular and/or lymph node invasion. E-cadherin and vimentin expressions were semi-quantitated for positive- cancer cells (0=0-<1%, 1=1-10%, 2 =11-50%, 3=>50%) and staining intensity (0=negative, 1=weak, 2=moderate, 3=strong), with final score (low=0-4 and high=6-9) derived by multiplying percentage and intensity scores for each marker. Low E-cadherin and/or high vimentin scores defined EMT positivity. Low E-cadherin co-existing with high vimentin defined "complete" (EMT-CV), while low E-cadherin (EMT-C) or high vimentin (EMT-V) occurring independently defined "partial" subsets. 38 (31.9%) cancers expressed EMT, while 59.2 % TN, 13.3% luminal and 12% HER2-enriched cancers expressed EMT (p<0.05). Among the cancers with lymphovascular and/or lymph node invasion, EMT positivity by molecular types were 66.7% TN, 7.4% luminal and 11.8% HER2-enriched (p<0.05). Although EMT-V, associated with stem-cell properties was the dominant TN EMT profile, EMT-CV, a profile linked to vascular metastases, was encountered only in TN. EMT appears important in TN cancer and different EMT profiles may be associated with its aggressive nature.
FISHing for 1p19q codel in oligodendroglioma

Kong PL, Cheah PL, Mun KS, Chiew SF, Lau TP, Koh CC, et al.

Malays J Pathol, 2020 Dec;42(3):369-376.
PMID: 33361717

Together with isocitrate dehydrogenase (IDH) mutation, co-deletion of 1p19q (1p19q codel) is a prerequisite for diagnosis of oligodendroglioma, making it imperative that histopathology laboratories introduce testing for 1p19q codel. To date there is still no consensus reference range and cut-offs that confirm deletion of 1p or 19q. We embarked on determining our reference range in 11 formalinfixed, paraffin-embedded non-neoplastic brain tissue using fluorescence in situ hybridisation (FISH) with the Vysis 1p36/1q25 and 19q13/19p13 FISH Probe Kit (Abbott Molecular Inc., USA). At same time we attempted to validate our methodology in 13 histologically-confirmed IDH-mutant oligodendrogliomas. For 1p, percentage cells with deletion (range=8-23%; mean±SD = 15.73±5.50%) and target: control (1p36:1q25) ratio (range = 0.89-0.96; mean±SD = 0.92±0.03) in non-neoplastic brain, differed significantly (p<0.000) from oligodendroglioma (percentage cells with deletion: range = 49-100%; mean±SD = 82.46±15.21%; target:control ratio range:0.50-0.76; mean±SD = 0.59±0.08). For 19q, percentage cells with deletion (range = 7-20%; mean±SD = 12.00±3.49%) and target:control (19q13/19p13) ratio (range:0.90-0.97; mean±SD = 0.94±0.02) in non-neoplastic brain also differed significantly from oligodendroglioma (percentage cells with deletion: range = 45-100%; mean±SD = 82.62±18.13%; target:control ratio range:0.50-0.78; mean±SD = 0.59±0.09). Using recommended calculation method, for diagnosis of 1p deletion, percentage of cells showing deletion should be >32-33% and/or target:control ratio <0.83. For 19q, percentage of cells showing deletion should be >22% and target:control ratio <0.88. Using these cut-offs all 13 oligodendroglioma demonstrated 1p19q codel.
Fulltext Structural Studies of Epithelial Mesenchymal Transition Breast Tissues

Mohd Sobri SN, Abdul Sani SF, Sabtu SN, Looi LM, Chiew SF, Pathmanathan D, et al.

Sci Rep, 2020 02 06;10(1):1997.
PMID: 32029810 DOI: 10.1038/s41598-020-58932-5

At the supramolecular level, the proliferation of invasive ductal carcinoma through breast tissue is beyond the range of standard histopathology identification. Using synchrotron small angle x-ray scattering (SAXS) techniques, determining nanometer scale structural changes in breast tissue has been demonstrated to allow discrimination between different tissue types. From a total of 22 patients undergoing symptomatic investigations, different category breast tissue samples were obtained in use of surgically removed tissue, including non-lesional, benign and malignant tumour. Structural components of the tissues were examined at momentum transfer values between q = 0.2 nm-1 and 1.5 nm-1. From the SAXS patterns, axial d-spacing and diffuse scattering intensity were observed to provide the greatest discrimination between the various tissue types, specifically in regard to the epithelial mesenchymal transition (EMT) structural component in malignant tissue. In non-lesional tissue the axial period of collagen is within the range 63.6-63.7 nm (formalin fixed paraffin embedded (FFPE) dewaxed) and 63.4 (formalin fixed), being 0.9 nm smaller than in EMT cancer-invaded regions. The overall intensity of scattering from cancerous regions is a degree of magnitude greater in cancer-invaded regions. Present work has found that the d-spacing of the EMT positive breast cancer tissue (FFPE (dewaxed)) is within the range 64.5-64.7 nm corresponding to the 9th and 10th order peaks. Of particular note in regard to formalin fixation of samples is that no alteration is observed to occur in the relative differences in collagen d-spacing between non-lesional and malignant tissues. This is a matter of great importance given that preserved-sample and also retrospective study of samples is greatly facilitated by formalin fixation. Present results indicate that as aids in tissue diagnosis SAXS is capable of distinguishing areas of invasion by disease as well as delivering further information at the supramolecular level.
A review: Exploring the metabolic and structural characterisation of beta pleated amyloid fibril in human tissue using Raman spectrometry and SAXS

Mohd Nor Ihsan NS, Abdul Sani SF, Looi LM, Cheah PL, Chiew SF, Pathmanathan D, et al.

Prog Biophys Mol Biol, 2023 Sep;182:59-74.
PMID: 37307955 DOI: 10.1016/j.pbiomolbio.2023.06.002

Amyloidosis is a deleterious condition caused by abnormal amyloid fibril build-up in living tissues. To date, 42 proteins that are linked to amyloid fibrils have been discovered. Amyloid fibril structure variation can affect the severity, progression rate, or clinical symptoms of amyloidosis. Since amyloid fibril build-up is the primary pathological basis for various neurodegenerative illnesses, characterization of these deadly proteins, particularly utilising optical techniques have been a focus. Spectroscopy techniques provide significant non-invasive platforms for the investigation of the structure and conformation of amyloid fibrils, offering a wide spectrum of analyses ranging from nanometric to micrometric size scales. Even though this area of study has been intensively explored, there still remain aspects of amyloid fibrillization that are not fully known, a matter hindering progress in treating and curing amyloidosis. This review aims to provide recent updates and comprehensive information on optical techniques for metabolic and proteomic characterization of β-pleated amyloid fibrils found in human tissue with thorough literature analysis of publications. Raman spectroscopy and SAXS are well established experimental methods for study of structural properties of biomaterials. With suitable models, they offer extended information for valid proteomic analysis under physiologically relevant conditions. This review points to evidence that despite limitations, these techniques are able to provide for the necessary output and proteomics indication in order to extrapolate the aetiology of amyloid fibrils for reliable diagnostic purposes. Our metabolic database may also contribute to elucidating the nature and function of the amyloid proteome in development and clearance of amyloid diseases.
EDXRF and the relative presence of K, Ca, Fe and as in amyloidogenic tissues

Mohd Nor Ihsan NS, Abdul Sani SF, Looi LM, Pathmanathan D, Cheah PL, Chiew SF, et al.

Spectrochim Acta A Mol Biomol Spectrosc, 2024 Mar 05;308:123743.
PMID: 38113556 DOI: 10.1016/j.saa.2023.123743

Trace and minor elements play crucial roles in a variety of biological processes, including amyloid fibrils formation. Mechanisms include activation or inhibition of enzymatic reactions, competition between elements and metal proteins for binding positions, also changes to the permeability of cellular membranes. These may influence carcinogenic processes, with trace and minor element concentrations in normal and amyloid tissues potentially aiding in cancer diagnosis and etiology. With the analytical capability of the spectroscopic technique X-ray fluorescence (XRF), this can be used to detect and quantify the presence of elements in amyloid characterization, two of the trace elements known to be associated with amyloid fibrils. In present work, involving samples from a total of 22 subjects, samples of normal and amyloid-containing tissues of heart, kidney, thyroid, and other tissue organs were obtained, analyzed via energy-dispersive X-ray fluorescence (EDXRF). The elemental distribution of potassium (K), calcium (Ca), arsenic (As), and iron (Fe) was examined in both normal and amyloidogenic tissues using perpetual thin slices. In amyloidogenic tissues the levels of K, Ca, and Fe were found to be less than in corresponding normal tissues. Moreover, the presence of As was only observed in amyloidogenic samples; in a few cases in which there was an absence of As, amyloid samples were found to contain Fe. Analysis of arsenic in amyloid plaques has previously been difficult, often producing contradictory results. Using the present EDXRF facility we could distinguish between amyloidogenic and normal samples, with potential correlations in respect of the presence or concentration of specific elements.