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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.
Fulltext Predictors of Acquired T790M Mutation in Patients Failing First- or Second-Generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors

Chai CS, Liam CK, Poh ME, Ong DB, Pang YK, Cheah PL, et al.

Cancer Manag Res, 2020;12:5439-5450.
PMID: 32753961 DOI: 10.2147/CMAR.S253760

BACKGROUND: This study aims to determine the predictors of acquired exon 20 T790M mutation in advanced non-small cell lung cancer (NSCLC) patients harbouring sensitizing epidermal growth factor receptor (EGFR) mutation following the failure of first- or second-generation EGFR-tyrosine kinase inhibitor (TKI).
METHODS: This is a retrospective observational study of NSCLC patients with sensitising EGFR mutation experiencing disease progression (PD) whilst on first- or second-generation EGFR-TKIs with subsequent investigations to detect acquired T790M mutation at the University of Malaya Medical Centre from 1st January 2015 to 31st December 2017.
RESULTS: A total of 87 patients were included. Upon PD, acquired T790M mutation was found in 55 (63.2%) patients and was significantly more common in patients who achieved partial response (PR) whilst on the EGFR-TKIs (p = 0.008) or had new lung metastasis upon PD (p = 0.048). It was less frequent in patients who developed new symptomatic brain lesions (p = 0.021). Patients with exon 19 deletion were more likely to acquire T790M mutation compared to those with exon 21 L858R point mutation (p = 0.077). Multivariate analysis revealed PR whilst on EGFR-TKI treatment was an independent predictor of acquiring T790M mutation (p = 0.021), whereas development of new symptomatic brain lesions (p = 0.034) or new lymph node metastases (p = 0.038) upon PD was independently against acquiring T790M mutation. Patients with exon 19 deletion were more likely to acquire T790M mutation compared to those with exon 21 L858R point mutation (odds ratio: 2.3, 95% confidence interval: 0.84-6.25, p = 0.104).
CONCLUSION: The best tumour response of PR to first- or second-generation EGFR-TKI treatment independently predicts acquired T790M mutation. Patients with exon 19 deletion are likely to acquire T790M mutation. This would prove useful for clinicians to prognosticate and plan subsequent treatments for patients with advanced NSCLC harbouring EGFR mutations.
The immunohistochemistry signature of mismatch repair (MMR) proteins in a multiethnic Asian cohort with endometrial carcinoma

Woo YL, Cheah PL, Shahruddin SI, Omar SZ, Arends M

Int J Gynecol Pathol, 2014 Nov;33(6):554-9.
PMID: 25272293 DOI: 10.1097/PGP.0000000000000099

Endometrial cancer is the most common gynecologic cancer in developed countries and is rising in incidence globally. Although the 5-year survival rates are >80%, factors beyond conventional pathologic features that predict clinical outcomes are still being elucidated. The aims of this study were to define the prevalence and associations of deficient mismatch repair (dMMR) protein expression (MLH1, MSH2, MSH6, PMS2) by immunohistochemistry in a multiethnic Southeast Asian cohort with endometrioid endometrial cancer. A total of 77 patients with adequate formalin-fixed paraffin-embedded specimens were identified. The sections were stained in 2 centers for 4 MMR proteins and examined by 2 independent specialist histopathologists. The mean age for the cohort was 58.6 yr, with 19.4% (15/77) of patients' cancers showing loss of 2 MMR proteins. All 13 cancers with absent MLH1 showed PMS2 loss (13/15), whereas absent MSH2 correlated with MHS6 loss (2/15). There were no significant differences for dMMR cases in age, body mass index, histopathologic characteristics, and clinical outcomes. In dMMR cases, an overrepresentation of patients of Indian ethnic origin was observed compared with Chinese and Malays. These findings suggest that dMMR protein expression in a Southeast Asian endometrial cancer cohort does not correlate with disease outcomes.
Fulltext DNA mismatch repair and CD133-marked cancer stem cells in colorectal carcinoma

Cheah PL, Li J, Looi LM, Teoh KH, Ong DB, Arends MJ

PeerJ, 2018;6:e5530.
PMID: 30221090 DOI: 10.7717/peerj.5530

Background: Except for a few studies with contradictory observations, information is lacking on the possibility of association between DNA mismatch repair (MMR) status and the presence of cancer stem cells in colorectal carcinoma (CRC), two important aspects in colorectal carcinogenesis.
Methods: Eighty (40 right-sided and 40 left-sided) formalin-fixed, paraffin-embedded primary CRC were immunohistochemically studied for CD133, a putative CRC stem cell marker, and MMR proteins MLH1, MSH2, MSH6 and PMS2. CD133 expression was semi-quantitated for proportion of tumor immunopositivity on a scale of 0-5 and staining intensity on a scale of 0-3 with a final score (units) being the product of proportion and intensity of tumor staining. The tumor was considered immunopositive only when the tumor demonstrated moderate to strong intensity of CD133 staining (a decision made after analysis of CD133 expression in normal colon). Deficient MMR (dMMR) was interpreted as unequivocal loss of tumor nuclear staining for any MMR protein despite immunoreactivity in the internal positive controls.
Results: CD133 was expressed in 36 (90.0%) left-sided and 28 (70.0%) right-sided tumors (p 0.05).
Conclusion: Proficient MMR correlated with high levels of CD133-marked putative cancer stem cells in both right- and left-sided tumors, whereas significantly lower levels of CD133-marked putative cancer stem cells were associated with deficient MMR status in colorectal carcinomas found on the right.
Fulltext Description, molecular characteristics and Wolbachia endosymbionts of Onchocerca borneensis Uni, Mat Udin & Takaoka n. sp. (Nematoda: Filarioidea) from the Bornean bearded pig Sus barbatus Müller (Cetartiodactyla: Suidae) of Sarawak, Malaysia

Uni S, Mat Udin AS, Agatsuma T, Junker K, Saijuntha W, Bunchom N, et al.

Parasit Vectors, 2020 Feb 06;13(1):50.
PMID: 32028994 DOI: 10.1186/s13071-020-3907-8

BACKGROUND: The genus Onchocerca Diesing, 1841 includes species of medical importance, such as O. volvulus (Leuckart, 1893), which causes river blindness in the tropics. Recently, zoonotic onchocercosis has been reported in humans worldwide. In Japan, O. dewittei japonica Uni, Bain & Takaoka, 2001 from wild boars is a causative agent for this zoonosis. Many filarioid nematodes are infected with Wolbachia endosymbionts which exhibit various evolutionary relationships with their hosts. While investigating the filarial fauna of Borneo, we discovered an undescribed Onchocerca species in the bearded pig Sus barbatus Müller (Cetartiodactyla: Suidae).
METHODS: We isolated Onchocerca specimens from bearded pigs and examined their morphology. For comparative material, we collected fresh specimens of O. d. dewittei Bain, Ramachandran, Petter & Mak, 1977 from banded pigs (S. scrofa vittatus Boie) in Peninsular Malaysia. Partial sequences of three different genes (two mitochondrial genes, cox1 and 12S rRNA, and one nuclear ITS region) of these filarioids were analysed. By multi-locus sequence analyses based on six genes (16S rDNA, ftsZ, dnaA, coxA, fbpA and gatB) of Wolbachia, we determined the supergroups in the specimens from bearded pigs and those of O. d. dewittei.
RESULTS: Onchocerca borneensis Uni, Mat Udin & Takaoka n. sp. is described on the basis of morphological characteristics and its genetic divergence from congeners. Molecular characteristics of the new species revealed its close evolutionary relationship with O. d. dewittei. Calculated p-distance for the cox1 gene sequences between O. borneensis n. sp. and O. d. dewittei was 5.9%, while that between O. d. dewittei and O. d. japonica was 7.6%. No intraspecific genetic variation was found for the new species. Wolbachia strains identified in the new species and O. d. dewittei belonged to supergroup C and are closely related.
CONCLUSIONS: Our molecular analyses of filarioids from Asian suids indicate that the new species is sister to O. d. dewittei. On the basis of its morphological and molecular characteristics, we propose to elevate O. d. japonica to species level as O. japonica Uni, Bain & Takaoka, 2001. Coevolutionary relationships exist between the Wolbachia strains and their filarial hosts in Borneo and Peninsular Malaysia.
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.
Immunohistochemical expression of p53 proteins in Wilms' tumour: a possible association with the histological prognostic parameter of anaplasia

Cheah PL, Looi LM, Chan LL

Histopathology, 1996 Jan;28(1):49-54.
PMID: 8838120

Wilms' tumour (nephroblastoma) has been associated with chromosomal abnormalities at the 11p13, 11p15 and 16q regions. A study into the possibility of mutations occurring within p53, the ubiquitous adult tumour suppressor gene, in Wilms' tumour was carried out. Thirty-eight cases were studied. Of these 36 were categorised into the favourable histology group and two into the unfavourable histology group based on the National Wilms' Tumour Study criteria. Archival formalin-fixed, paraffin-embedded tissue sections from each case were stained with a polyclonal (AB565:Chemicon) and a monoclonal (DO7:Dako) antibody raised against p53 protein using a peroxidase-labelled streptavidin biotin kit (Dako). 'Cure' (disease-free survival of 60 months or longer) was documented in 39% of cases with favourable histology tumours. Eleven percent in this group succumbed to the disease. Both cases with unfavourable histology died. Four out of 36 (11%) tumours with favourable histology demonstrated weak to moderate staining with both AB565 and DO7 in more than 75% of tumour cells. In contrast, p53 protein expression in unfavourable histology tumours was significantly increased compared with the favourable histology group (P = 0.021) with both cases demonstrating immunopositivity in > 75% of tumour cells when stained with AB565 and DO7. The intensity of staining ranged from moderate to strong in both cases. It appears from this preliminary study that the immunohistochemical expression of p53 protein in Wilms' tumour, presumably a result of mutation in the p53 tumour suppressor gene, correlates with histological classification, histological categorisation being one of the useful features in the prognostic assessment of Wilms' tumours.
A review on omics-based biomarkers discovery for Alzheimer's disease from the bioinformatics perspectives: Statistical approach vs machine learning approach

Tan MS, Cheah PL, Chin AV, Looi LM, Chang SW

Comput Biol Med, 2021 12;139:104947.
PMID: 34678481 DOI: 10.1016/j.compbiomed.2021.104947

Alzheimer's Disease (AD) is a neurodegenerative disease that affects cognition and is the most common cause of dementia in the elderly. As the number of elderly individuals increases globally, the incidence and prevalence of AD are expected to increase. At present, AD is diagnosed clinically, according to accepted criteria. The essential elements in the diagnosis of AD include a patients history, a physical examination and neuropsychological testing, in addition to appropriate investigations such as neuroimaging. The omics-based approach is an emerging field of study that may not only aid in the diagnosis of AD but also facilitate the exploration of factors that influence the development of the disease. Omics techniques, including genomics, transcriptomics, proteomics and metabolomics, may reveal the pathways that lead to neuronal death and identify biomolecular markers associated with AD. This will further facilitate an understanding of AD neuropathology. In this review, omics-based approaches that were implemented in studies on AD were assessed from a bioinformatics perspective. Current state-of-the-art statistical and machine learning approaches used in the single omics analysis of AD were compared based on correlations of variants, differential expression, functional analysis and network analysis. This was followed by a review of the approaches used in the integration and analysis of multi-omics of AD. The strengths and limitations of multi-omics analysis methods were explored and the issues and challenges associated with omics studies of AD were highlighted. Lastly, future studies in this area of research were justified.
Fulltext A comparison of 1995 WHO classification with 2003 ISN/RPS classification of lupus nephritis: a single centre observation

Chow TK, Looi LM, Cheah PL

Malays J Pathol, 2015 Dec;37(3):239-46.
PMID: 26712669

BACKGROUND: In the past, lupus nephritis was histologically classified according to the 1995 WHO Classification. With the introduction of the 2003 ISN/RPS Classification, many nephropathology services converted to this new classification. This study was undertaken to compare both classification systems in a single centre practice.
METHODS: 103 consecutive adequate renal biopsies initially reported as lupus nephritis in the Department of Pathology, Faculty of Medicine, University of Malaya were reassessed using the criteria of both the 1995 WHO Classification and the 2003 ISN/ RPS Classification.
RESULTS: The relative prevalence for each class using the WHO Classification were: Class I (1%), Class II (8.7%), Class III (6.8%), Class IV (60.2%), Class V (20.4%), Class VI (2.9%) while the prevalence using the 2003 ISN/RPS Classification were: Class I (1%), Class II (8.7%), Class III (6.8%), Class IV (61.2%), Class V (21.3%), Class VI (1%). Both classifications were essentially comparable with regards to Classes I, II and III. The differences in Classes IV, V and VI were significant in potential to alter patient management. The identification of segmental lesions (Class IV-S) over and above a global nephritis (Class IV-G) deserves more focused clinicopathological studies to gauge whether these groups have different clinical manifestations and outcomes. With regards Class V, the ISN/RPS system, by requiring that all mixed classes be stipulated in the diagnostic line, minimizes the chances of patients missing out on additional treatment. The ISN/ RPS system has stricter criteria for Class VI, which again minimizes patients missing out on therapy. On the whole, the ISN/RPS system is more user-friendly as criteria are more clearly defined which translates to more benefits to patient care.
Study site: Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Tissue microarray immunohistochemical profiles of p53 and pRB in hepatocellular carcinoma and hepatoblastoma

Azlin AH, Looi LM, Cheah PL

Asian Pac J Cancer Prev, 2014;15(9):3959-63.
PMID: 24935581

The tumour suppressor genes, p53 and pRb, are known to play important roles in neoplastic transformation. While molecular routes to the uncontrolled growth of hepatocytes, leading to primary liver cancer have generated considerable interest, the roles of p53 and pRb mutations in hepatocellular carcinoma (HCC) and hepatoblastoma (HB) remain to be clarified. We examined the immunohistochemical expression of p53 and pRb gene products in 26 HCC and 9 HB, sampled into tissue microarray blocks. 10 (38%) of 26 HCC showed > 10% tumour nuclear staining for p53 protein, 3 of these also being HbsAg positive. Conversely, none of 9 HB expressed nuclear p53 immunopositivity. Some 24 (92%) HCC and 8 (89%) HB showed loss of pRb nuclear expression. Two of the 26 HCC and one of the 9 HB showed >10% tumour nuclear staining for pRb protein. Our results suggest that p53 does not have an important role in the development of HB but may contribute in HCC. There is also loss of pRb expression in the majority of HCC and HB, supporting loss of pRb gene function in the hepatocarcinogenesis pathway. However, a comparison of the staining profiles of p53 and pRb proteins in HCC and HB did not reveal a consistent pattern to differentiate between the two types of tumours immunohistochemically. Hence the use of p53 and pRB protein expression has no contribution in the situation where there is a diagnostic difficulty in deciding between HCC and HB.
Performance of transient elastography (TE) and factors associated with discordance in non-alcoholic fatty liver disease

Mahadeva S, Mahfudz AS, Vijayanathan A, Goh KL, Kulenthran A, Cheah PL

J Dig Dis, 2013 Nov;14(11):604-10.
PMID: 23859493 DOI: 10.1111/1751-2980.12088

To determine the accuracy of transient elastography (TE) and factors associated with discordance between TE and liver histology in patients with non-alcoholic fatty liver disease (NAFLD).
Fulltext CD133 marks for colorectal adenocarcinoma

Chew MF, Teoh KH, Cheah PL

Malays J Pathol, 2012 Jun;34(1):25-8.
PMID: 22870594 MyJurnal

CD133, a marker which has been advocated to mark colorectal carcinoma "stem or tumour initiating cells" is amongst the frequently studied markers in colorectal cancer. A study was conducted at the Department of Pathology, University of Malaya Medical Centre to determine the expression of CD133 in 56 archived, formalin-fixed, paraffin-embedded colorectal adenocarcinoma in comparison with adjacent benign colorectal epithelium by immunohistochemical staining for CD133 expression. CD133 immunopositivity was determined as staining at the glandular luminal surface or in the intraluminal debris. Expression was semiquantitated for (1) proportion of CD133 immunopositivity in the malignant or adjacent benign colorectal epithelium and (2) intensity of staining. The final score of CD133 immunopositivity was arbitrarily taken as proportion of CD133 immunopositivity multiplied by intensity of staining in both the malignant and adjacent benign colorectal epithelium. CD133 expression was observed in significantly increased frequency in 49 (87.5%) colorectal adenocarcinoma compared with 15 (26.8%) of the adjacent benign colorectal epithelium (p<0.05). In terms of immunopositivity score (proportion of CD133 immunopositivity multiplied by intensity of staining), colorectal adenocarcinoma had a mean arbitrary score of 8.5 which was significantly higher than the mean immunopositivity score of 0.5 of the adjacent benign colorectal epithelium (p<0.05). In addition, the maximum immunopositivity score for the adjacent benign colorectal epithelium was 4, while 38 (67.9%) of colorectal adenocarcinoma had scores >4. This study shows that CD133 is able to mark colorectal adenocarcinoma but it is still unclear at this juncture whether CD133 is indeed a marker for colorectal adenocarcinoma "stem cells".
Fulltext Historical development of the renal histopathology services in Malaysia

Looi LM, Cheah PL

Malays J Pathol, 2009 Jun;31(1):11-6.
PMID: 19694308 MyJurnal

Western-style medicine was introduced to Malaya by the Portuguese, Dutch and British between the 1500s and 1800s. Although the earliest pathology laboratories were developed within hospitals towards the end of the 19th Century, histopathology emerged much later than the biochemistry and bacteriology services. The University Departments of Pathology were the pioneers of the renal histopathology diagnostic services. The Department of Pathology, University of Malaya (UM) received its first renal biopsy on 19 May 1968. Hospital Universiti Kebangsaan Malaysia (HUKM) and Hospital Universiti Sains Malaysia (HUSM) started their services in 1979 and 1987 respectively. It is notable that the early services in these University centres caterred for both the university hospitals and the Ministry of Health (MOH) until the mid-1990s when MOH began to develop its own services, pivoted on renal pathologists trained through Fellowship programmes. Currently, key centres in the MOH are Kuala Lumpur Hospital, Sultanah Aminah Hospital Johor Bahru and Malacca Hospital. With the inclusion of renal biopsy interpretation in the Master of Pathology programmes, basic renal histopathology services became widely available throughout the country from 2000. This subsequently filtered out to the private sector as more histopathologists embraced private practice. There is now active continuing professional development in renal histopathology through clinicopathological dicussions, seminars and workshops. Renal research on amyloid nephropathy, minimal change disease, IgA nephropathy, fibrillary glomerulonephritis, lupus nephritis and microwave technology have provided an insight into the patterns of renal pathology and changing criteria for biopsy. More recently, there has been increasing involvement of renal teams in clinical trials, particularly for lupus nephritis and renal transplant modulation.
Fulltext Telomerase activation in neoplastic cell immortalization and tumour progression

Looi LM, Ng MH, Cheah PL

Malays J Pathol, 2007 Jun;29(1):33-5.
PMID: 19105326 MyJurnal

The unique ability of tumour cells to proliferate indefinitely is crucial to neoplastic progression as it allows these cells to express the aggressive properties of cancer without the censure of physiological ageing. This is in contrast to normal somatic cells which are subject to a "mitotic clock," a phenomenon that has been linked to telomeric shortening after each round of cell replication, so that eventually the loss of genetic material reaches a critical stage and the cells undergo senescence and cell death. A study was conducted to investigate the role of telomerase, an RNA-containing enzyme that restores the telomere length, in the neoplastic cell immortalization and progression process. Fresh human tissue samples taken from excision specimens received by the Department of Pathology, University of Malaya Medical Centre, were investigated for telomerase activity using a commercial Telomerase PCR-ELISA kit (Boehringer Mannheim). Specimens comprised 33 breast lesions (10 infiltrating breast adenocarcinoma, 13 fibroadenoma and 10 non-neoplastic breast tissue), 27 colonic lesions (17 colonic adenocarcinoma and 10 non-neoplastic colonic mucosa) and 42 cervical lesions (20 cervical carcinoma and 22 non-neoplastic cervical tissues). Telomerase activity was found in 6 (60%) of 10 breast carcinomas, 6 (46%) of 13 fibroadenomas, none of the 10 nonneoplastic breast samples, 3 (17.6%) of 17 colon carcinomas and none of the 10 non-neoplastic colonic mucosal samples, 12 (60%) of 20 cervical carcinoma and 3 (13.6%) of 22 non-neoplastic cervical samples. 5/10 (50%) Stage I, 4/7 (57%) Stage II, 2/2 (100%) Stage III and 1/1 (100%) Stage IV cervical carcinomas showed telomerase activity. These findings support a contributory role for telomerase in tumourigenesis with activation occurring from neoplastic transformation and increasing with tumour progression.
C-erbB-2 oncoprotein amplification in infiltrating ductal carcinoma of breast relates to high histological grade and loss of oestrogen receptor protein

Looi LM, Cheah PL

Malays J Pathol, 1998 Jun;20(1):19-23.
PMID: 10879259

Eighty-six infiltrating ductal carcinoma of breast were studied by the standard avidin-biotin complex immunoperoxidase method on formalin-fixed, paraffin-embedded tissue sections, for oestrogen receptor (ER) protein and c-erbB-2 oncoprotein expression. They were categorized according to the modified Bloom and Richardson criteria into three histological grades. 21% tumours were ER positive while 44% were c-erbB-2 positive. Of ER positive tumours, 33.3% were c-erbB-2 positive whereas the c-erbB-2 positivity rate was much higher (47.1%) in ER negative tumours. Only 16% of c-erbB-2 positive tumours were ER positive while 25% of c-erbB-2 negative tumours were ER positive. This negative relationship between ER and c-erbB-2 expression was statistically significant (Mc Nemar's test, p < 0.005). The ER positivity rate did not vary significantly with histological grade. However, c-erbB-2 overexpression was significantly more prevalent in grade III tumours compared with grade I and II tumours (Chi-square test, p < 0.005). Since the c-erbB-2 oncogene has extensive structural homology to the epidermal growth factor receptor (EGFR) gene, we expect that c-erbB-2 oncoprotein would share functional similarities with EGFR leading to both loss of oestrogen receptor and poor prognosis in breast cancer. Its overexpression can be expected to relate to more aggressive tumour proliferation and may explain its correlation with high histological grade, a known indicator of aggressive cancer behaviour. As there is no indication that ER protein activity contributes to advancement in histological grade, it would appear that cellular dedifferentiation precedes ER loss during malignant transformation. It has been mooted that ER positive breast cancers which also show c-erbB-2 oncoprotein overexpression have a poorer response to hormonal therapy. The use of this parameter in the routine assessment of breast cancer patients may identify subsets of patients for more aggressive therapy.
Histomorphological patterns of renal amyloidosis: a correlation between histology and chemical type of amyloidosis

Looi LM, Cheah PL

Hum Pathol, 1997 Jul;28(7):847-9.
PMID: 9224755

A retrospective study was conducted to investigate whether there was a correlation between the histological pattern of renal amyloidosis, the chemical type of amyloid protein involved and the clinical presentation. Eighteen consecutive cases of systemic amyloidosis that had renal biopsies processed and examined histopathologically at the Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur were reviewed. The age range of patients was 25 to 64 yrs (mean, 46 yrs). The male:female ratio was 2.6:1. Three patients were Malay, 9 Chinese, 3 Indian, 1 Indonesian, 1 Iban, and 1 Bisaya. According to the predominant site of amyloid deposition, 14 cases showed a glomerular pattern and 4 a vascular pattern. 8 cases were designated as 2 anti-human amyloid-A (AA) amyloidosis on the basis of permanganate-sensitivity and immunoreactivity of deposits with anti-human AA protein antibody. Ten cases contained deposits that were permanganate-resistant and nonimmunoreactive for AA protein and were designated as AL in type. The histomorphologic pattern of renal amyloidosis did not provide a reliable means of differentiating AA from AL amyloidosis. The glomerular pattern tended to present with renal manifestations such as nephrotic syndrome and chronic renal failure, whereas the vascular pattern tended to present with nonrenal manifestations such as diarrhoea. These findings may have a bearing on the pathophysiology of amyloidosis and provide clues to appropriate management.
Correlation between oestrogen receptor protein expression in infiltrating ductal carcinoma of the breast by immunohistochemistry and cytosol measurements

Looi LM, Yap SF, Cheah PL

Ann Acad Med Singap, 1997 Nov;26(6):750-3.
PMID: 9522973

Fresh frozen neoplastic tissues from 70 infiltrating ductal breast carcinomas were analysed for cytosolic oestrogen receptor (ER) protein content using a solid phase enzyme immunoassay (EIA) method based on a "sandwich" principle (Abbott ER-EIA monoclonal). Formalin-fixed, paraffin-embedded sections from the same carcinomas were examined for nuclear immunoreactivity against a monoclonal antibody for ER protein (Dako) using the standard avidin-biotin complex immunoperoxidase (IP) method after microwave antigen retrieval. The degree of ER positivity by IP was also scored according to a visual estimation of the percentage of cells expressing immunopositivity and the intensity of staining. Twenty-eight (40%) of the carcinomas were ER-positive by EIA and 34 (48.6%) were positive by IP. Twenty-five (35.7%) were ER-positive and 33 (47.1%) were ER-negative by both methods. Nine (12.9%) were ER-negative by EIA but were positive by IP, this discrepancy being ascribed to sampling inadequacy for EIA. However, 3 (4.3%) tumours were ER-positive by EIA and negative by IP. This discrepancy may be variously due to inadequate antigen retrieval, faulty technique and the possibility that the two methods do not measure identical ER proteins. IP appears to have an advantage over EIA in that it has a higher pick-up rate, does not require fresh tissue and can be applied to archival material. However, to reduce false negative estimations, it may be necessary to run IP staining using more than one ER antibody. Standardisation of the IP method for ER is desirable before this method is to be widely adopted in Malaysian laboratories. Quantitation of ER positivity by IP scoring correlated poorly with actual cytosolic levels. Caution should be exercised in attaching patient management value to visual IP scoring.
Human papillomavirus related diseases in Malaysians

Cheah PL

Malays J Pathol, 1994 Jun;16(1):15-7.
PMID: 16329570

The surge of information on the aetiological association of the human papillomavirus (HPV) with some epithelial tumours emanating from various centres has prompted the initiation of a large-scale retrospective study at the Department of Pathology, University Hospital Kuala Lumpur to determine the prevalence and importance of this virus in some epithelial tumours of Malaysian patients. A retrospective analysis of 100 cases of large cell non-keratinising carcinoma of the uterine cervix by in-situ hybridisation on archival formalin-fixed, paraffin-embedded tissue has revealed the presence of HPV type 16 in 47% and type 18 in 41% of cases. This gives an overall detection rate of 88% of the two HPV types most commonly encountered in cervical carcinomas. Except for the unusually high frequency of HPV 18 detected in the cases, the overall prevalence is comparable to that reported in studies from most other centres. Although this higher frequency of HPV 18 may be due to geographical variation, the selection of the large cell non-keratinising type of squamous cell cervical carcinoma for study remains a possible reason for this phenomenon. In comparison to cervical carcinomas, HPV appears to be uncommon in penile carcinomas and HPV 6 was detected in only 1 of 23 cases studied.
Rare case of huge retroperitoneal liposarcoma presenting as a gynaecological problem

Kuppuvelumani P, Rachagan SP, Syed N, Kumar G, Cheah PL

Eur J Obstet Gynecol Reprod Biol, 1993 Mar;48(3):220-2.
PMID: 8335141

A large retroperitoneal liposarcoma presented clinically as an ovarian tumour in an infertile woman. The importance of computed tomography in the differential diagnosis and the appropriate management of retroperitoneal liposarcoma is presented with a review of the relevant literature.

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