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Fulltext Correlation of p16INK4a immunoexpression and human papillomavirus (HPV) detected by in-situ hybridization in cervical squamous neoplasia

Cheah PL, Koh CC, Nazarina AR, Teoh KH, Looi LM

Malays J Pathol, 2016 Apr;38(1):33-8.
PMID: 27126662 MyJurnal

Persistence and eventual integration of high-risk HPV (hrHPV) into the cervical cell is crucial to the progression of cervical neoplasia and it would be beneficial to morphologically identify this transformation in routine surgical pathology practice. Increased p16(INK4a) (p16) expression is a downstream event following HPV E7 binding to pRB. A study was conducted to assess the correlation between hrHPV detection using a commercial in-situ hybridization assay (Ventana INFORM HPV ISH) and p16 immunoexpression (CINtec Histology Kit) in cervical squamous intraepithelial lesions and squamous carcinoma. 27 formalin-fixed, paraffin-embedded cervical low-grade squamous intraepithelial lesions (LSIL), 21 high-grade squamous intraepithelial lesions (HSIL) and 51 squamous carcinoma (SCC) were interrogated. hrHPV was significantly more frequent in HSIL (76.2%) and SCC (88.2%) compared to LSIL(37.0%). p16 expression was similarly more frequent in HSIL (95.2%) and SCC (90.2%) compared to LSIL(3.7%). That the rates of hrHPV when compared with p16 expression were almost equivalent in HSIL and SCC while p16 was expressed in only 1 of the 10 LSIL with hrHPV, are expected considering the likelihood that transformation has occurred in HSIL and SCC but does not occur in majority of LSIL.
Fulltext E-cadherin downregulation at the infiltrating tumour front is associated with histological grade and stage in colorectal carcinoma of Malaysians

Dass SD, Cheah PL, Ong DB, Teoh KH, Looi LM

Malays J Pathol, 2015 Apr;37(1):19-24.
PMID: 25890609 MyJurnal

Loss of E-cadherin, a 120 kDA transmembrane glycoprotein responsible for cell-cell adhesion, is one of the hallmarks of epithelial-mesenchymal-transition (EMT). E-cadherin expression was immunohistochemically studied in 94 histopathologically re-confirmed colorectal carcinomas (CRC) using a monoclonal antibody to E-cadherin (Dako: Clone NCH-38) on a Ventana Benchmark XT automated system. Each case was assessed for E-cadherin immunopositivity at two separate locations viz the tumour centre (TC) as well as the infiltrating front (IF). Expression was semiquantitated for proportion of immunopositive malignant cells as 0 (negative), 1 (1-25% staining), 2 (26-50% staining), 3 (51-75% staining) and 4 (>75% staining) and staining intensity: 0 (negative), 1 (weak), 2 (moderate) and 3 (strong). The final histoscore of E-cadherin immunopositivity was arbitrarily computed as proportion of immunopositivity multiplied by staining intensity of the malignant cells. E-cadherin histoscores were significantly lower at the IF (4.5 ± 2.5) compared with TC (10.7 ± 2.4). Furthermore, the histoscores were significantly reduced at the IF of 49 TNM III+IV tumours (3.6 ± 2.5) compared with 45 II+III CRC (5.4 ± 2.2). Reduction of E-cadherin expression was also noted in the 23 high grade (TC=8.6 ± 3.2; IF=2.6 ± 2.3) compared with 71 low grade tumours (TC = 11.4 ± 1.5; IF = 5.1 ± 2.3). E-cadherin is downregulated at the infiltrating front of CRC, possibly marking for EMT at this location. The downregulation is further enhanced amongst late stage and high grade tumours compared with earlier stage and low grade tumours; findings which are similar to that noted in CRC of other populations.
Fulltext Carcinoma of the uterine cervix: a review of its pathology and commentary on the problem in Malaysians

Cheah PL, Looi LM

Malays J Pathol, 1999 Jun;21(1):1-15.
PMID: 10879274

Since its recognition about 150 years ago, there has been much progress in the understanding of the pathogenesis, prevention, early detection and management of carcinoma of the uterine cervix. Important historical landmarks include the (1) recognition of pre-invasive and pre-clinical lesions, and the devise of various systems for reporting these lesions, (2) improvements in diagnostic techniques particularly colposcopy, (3) advent of therapeutic procedures (electrocoagulation, cryotherapy, laser therapy and loop electrosurgical excision), and (4) recognition of the aetiological relationship between the human papillomavirus and cervical neoplasia. The susceptibility of the cervical transformation zone to malignant change is now well recognised. The WHO classification system remains the one most commonly utilised for histological reporting of cervical cancers. In the recent 1994 update, cervical carcinoma is divided into 3 main categories: squamous cell carcinoma, adenocarcinoma and other epithelial tumours. Squamous cell carcinoma (60-80%) predominates among invasive cervical carcinoma. Recognised variants include verrucous, warty (condylomatous), papillary squamous (transitional) and lymphoepithelioma-like carcinoma. Adenocarcinoma (5-15% of invasive carcinomas) shows an increasing trend in young females. Like its squamous counterpart, preinvasive and microinvasive versions are known. Variants such as mucinous, endometrioid, clear cell, mesonephric, serous, villoglandular and minimal deviation carcinoma are now defined. Adenosquamous carcinoma (5-25%), adenoid-cystic, adenoid-basal, neuroendocrine and undifferentiated carcinomas constitute other epithelial tumours of the cervix. The management of invasive cervical carcinoma remains heavily dependent on its stage. The FIGO staging system remains the most widely used. The 1995 update provides more definite criteria in subdividing stage IA tumours by delimiting stromal invasion of stage IA1 lesions to a maximum depth of 3 mm and a horizontal axis of 7 mm. In Malaysia, an appreciation of the cervical carcinoma problem has to take into consideration the population at risk, its multi-ethnicity, its socio-economic and geographical diversities and the constraints of the health care system. Females form 48.9% of the Malaysian population. 52.9% of them are in the sexually active age group of 15-50 years, indicating a significant population at risk for cervical carcinoma. Cervical carcinoma was the third most common cause of death due to solid tumours among Malaysian females in 1995 following carcinoma of the breast and respiratory tract. East Malaysia is predominantly rural with many communities having limited modern facilities. Such areas imply a lower educational and socio-economic status, raising the worry of a population at higher risk for developing cervical carcinoma. The population: doctor for Malaysia of 2153:1 compares poorly with nearby Singapore. Besides a shortage of doctors, there is also an uneven distribution of doctors, resulting in a ratio in East Malaysia of > 4000:1. Although Malaysia does not have a national cervical cancer-screening programme, many action plans and cancer awareness campaigns have been launched throughout the years, which appear to have made an impact as evidenced by the decreasing mortality rates from cervical carcinoma. Another interesting feature of cervical carcinoma in Malaysia relates to its multiethnic population. In Malaysian Chinese and Malay females, the prevalence of cervical carcinoma ranks second to breast cancer whereas the pattern is reversed in Malaysian Indian females. Studies into its aetiology and pathogenesis are being undertaken and may shed more light on this matter.
Immunotactoid glomerulopathy--an unusual deposition disease: report of the first Malaysian case

Cheah PL, Looi LM, Ghazalli R, Chua CT

Malays J Pathol, 1999 Jun;21(1):59-62.
PMID: 10879280

A 31-year-old Malay female presented with nephrotic syndrome without renal impairment. Renal biopsy features were in keeping with immunotactoid glomerulopathy (ITG). Non-Congophilic deposits were seen causing thickening of the glomerular capillary basement membrane with segmental accentuation, and widening of the mesangium. Immunofluorescence examination showed moderate amounts of IgG and C3 in the glomerular capillary walls with some in the mesangium. Ultrastructurally, 20-nm thick fibrils with microtubular organisation were present predominantly in the subendothelial region with similar fibrils in the mesangium. Although immunotactoid glomerulopathy and fibrillary glomerulonephritis (FG) have been recognised as entities with extracellular fibrillary material in the kidney, to date much remains to be clarified regarding these 2 conditions. While the renal biopsy findings in this patient are consistent with ITG, her clinical presentation is unlike that of usual ITG in that she is of a much younger age and has no associated haemopoietic disorder. Response to initial treatment of 8 weeks of prednisolone therapy was poor.
Fulltext Biology and pathological associations of the human papillomaviruses: a review

Cheah PL, Looi LM

Malays J Pathol, 1998 Jun;20(1):1-10.
PMID: 10879257

Historical cottontail rabbit papillomavirus studies raised early indications of a mammalian DNA oncogenic virus. Today, molecular cloning recognises numerous animal and human papillomaviruses (HPVs) and the development of in vitro transformation assays has escalated oncological research in HPVs. Currently, their detection and typing in tissues is usually by Southern blotting, in-situ hybridization and polymerase chain reaction methods. The complete papillomavirus virion constitutes a protein coat (capsid) surrounding a circular, double-stranded DNA organised into coding and non-coding regions. 8 early (E1-E8) open reading frames (ORFs) and 2 late (L1, L2) ORFs have been identified in the coding region of all papillomaviruses. The early ORFs encode proteins which interact with the host genome to produce new viral DNA while late ORFs are activated only after viral DNA replication and encode for viral capsid proteins. All papillomaviruses are obligatory intranuclear organisms with specific tropism for keratinocytes. Three possible courses of events can follow papillomaviruses entry into cells: (1) viral DNA are maintained as intranuclear, extrachromosomal, circular DNA episomes, which replicates synchronously with the host cell, establishing a latent infection; (2) conversion from latent into productive infection with assembly of complete infective virions; (3) integration of viral DNA into host cellular genome, a phenomenon seen in HPV infections associated with malignant transformation. Human papillomaviruses (HPVs) essentially induce skin and mucosal epithelial lesions. Various skin warts are well known to be HPV-associated (HPVs 1, 2, 3, 7 and 10). Besides HPVs 3 and 10, HPVs 5, 8, 17 and 20 have been recovered from Epidermodysplasia verruciformis lesions. Anogenital condyloma acuminatum, strongly linked with HPVs 6 and 11 are probably sexually transmitted. The same HPVs, demonstrable in recurrent juvenile laryngeal papillomas, are probably transmitted by passage through an infected birth canal. HPVs described in uterine cervical lesions are generally categorized into those associated with high (16, 18), intermediate (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) and low (6, 11, 26, 40, 42, 43, 44, 53, 54, 55, 62, 66) risk of cervical squamous carcinoma. Cervical adenocarcinoma, clear cell carcinoma and small cell neuroendocrine carcinoma have also been linked to HPVs, especially HPV18. Other lesions reported to be HPV-associated are: papillomas, dysplasia and carcinomas in the nasal cavity (HPV 6, 11, 57); squamous papilloma, condyloma acuminatum, and verruca vulgaris of the oral cavity (HPV 6, 11), oral focal epithelial hyperplasia (HPV 13, 32); warty lip lesions (HPV 2): and conjunctival papillomas (HPV 6, 11).
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.
Fulltext Enhanced major histocompatibility complex (MHC) class II antigen expression in lupus nephritis

Cheah PL, Looi LM, Chua CT, Yap SF, Fleming S

Malays J Pathol, 1997 Dec;19(2):115-20.
PMID: 10879251

Thirty-eight cases of lupus nephritis, all satisfying the American Rheumatism Association criteria for diagnosis of systemic lupus erythematosus (SLE), with renal involvement and biopsy were immunohistochemically studied for the expression of HLA-DR (DAKO: HLA-DR/alpha, TAL.1B5), one of the three known families belonging to the class II major histocompatibility complex (MHC), using a standard streptavidin-biotin-peroxidase method. 20 nephrectomies performed for renal trauma and tumours constituted the normal controls. Of the lupus nephritis cases, 34 were females and 4 males. Ethnically, 20 were Chinese, 13 Malay, 4 Indian and 1 of indigenous origin. Their ages ranged from 16 to 59 years (mean of 31 years). Histologically, 23 expressed World Health Organisation (WHO) class IV (diffuse proliferative), 10 WHO class V (diffuse membranous), 4 WHO class II (pure mesangiopathy) and 1 WHO class III (segmental and focal proliferative) nephritis. Activity scores ranged between 5 to 19 (mean = 8.6) and chronicity scored between 2 to 7 (mean = 3.2) on a standard scoring system. Similar to other studies, HLA-DR was expressed in the glomerular capillaries and peritubular capillaries of all and mesangium, tubules (proximal, distal and collecting), veins and arterioles of some normal controls. Interestingly, HLA-DR expression was noted in the arteries of 25% of the normal controls, a finding hitherto not reported. The frequency of lupus nephritis cases expressing HLA-DR in the various anatomical components did not differ significantly from the normal controls except that HLA-DR expression in arteries and arterioles was seen at a significantly increased frequency (p < 0.01) in lupus nephritis. This increased expression did not correlate with the WHO class, activity or chronicity scores. It therefore appears that MHC class II shows increased expression in the arterial system of lupus nephritis kidneys. The significance of this is unclear but could be related to heightened (gamma-interferon activation which may be a de novo phenomenon or result of T cell proliferation and activation in SLE.
Wilms' tumour in Malaysian children: a histopathological study of cases encountered at the University Hospital, Kuala Lumpur over a 22-year period

Cheah PL, Looi LM, Lin HP

Malays J Pathol, 1992 Dec;14(2):111-5.
PMID: 1338998

Formerly thought to have a constant incidence rate throughout the world, Wilms' tumour (nephroblastoma) has been shown to be less common among Asian children. A retrospective demographic and morphological study of Wilms' tumour histologically diagnosed over a 22-year period at the Department of Pathology, University Hospital, Kuala Lumpur was conducted to assess for inherent demographic and morphological differences between tumours in Malaysian children and those of Western populations. Thirty-seven cases of histologically proven Wilms' tumour qualified for inclusion in this study. 19 patients were Chinese, 13 Malay, 4 Indian and 1 Anglo-asian. 21 were male and 16 were female (M:F ratio = 1.3:1). Their ages ranged from 1 month to 4 years. 70.3% of the patients were below 2 years of age. 36 cases had unilateral and 1 bilateral tumours. Of unilateral tumours, 19 involved the left kidney and 17 the right. Histological assessment, based on criteria of the National Wilms' Tumor Study Group, revealed 20 (52.6%) tumours with a mixed pattern while 8 (21.1%) showed epithelial, 7 (18.4%) blastemal and 3 (7.8%) stromal-predominant patterns. Anaplasia was observed in only 2 tumours (5.3%). There was no obvious difference in age range and sex distribution, laterality of tumours and incidence of anaplasia between this and Western studies. No ethnic predilection was observed. A notably larger percentage of cases were below 2 years of age. Also, a larger proportion of epithelial-predominant and a lower proportion of blastemal-predominant tumours was observed compared with patterns reported from Western populations.
Correlation between histological grade and c-erbB2 oncoprotein overexpression in infiltrating ductal carcinoma of breast

Looi LM, Cheah PL, Yap SF

Malays J Pathol, 1997 Jun;19(1):35-9.
PMID: 10879240

One hundred and twelve infiltrating ductal carcinoma of breast were studied by the standard avidinbiotin complex immunoperoxidase method on formalin-fixed, paraffin-embedded tissue sections, using a monoclonal antibody to c-erbB-2 oncoprotein. The same tumours were assessed and scored according to the Bloom and Richardson criteria into three histological grades. The distribution of tumours according to grade were: 8 Grade I, 34 Grade II and 70 Grade III. Forty-three (38.4%) tumours showed positive membrane staining for c-erbB-2 oncoprotein. These comprised 7 Grade II and 36 Grade III tumours with c-erbB-2 immunopositivity rates of 20.6% and 51.4% respectively. The oncoprotein was not expressed by Grade I tumours. This study shows a good correlation between c-erbB-2 expression and histological grade, a known prognostic indicator of invasive breast carcinoma. Because the c-erbB-2 oncogene has extensive structural homology to the epidermal growth factor receptor gene, its overexpression can be expected to result in more aggressive tumour behaviour. While it may be regarded as another indicator of poor prognosis breast cancers, its value in the selection of carcinomas less responsive to hormonal therapy and those more suitable for immunotherapy than chemotherapy has been mooted but remains to be clarified.
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.
Alterations in mucin type: an indicator for suspicion of malignant gastric transformation

Cheah PL, Ramachandran K

Malays J Pathol, 1994 Jun;16(1):39-42.
PMID: 16329574

Mucins are produced by both benign and malignant gastric epithelium. In general, mucins can be classified into neutral and acidic mucins. The latter are of 2 major types, sulphated (sulphomucins) and carboxylated (sialomucins). A retrospective study was initiated at the Department of Pathology, University Hospital, Kuala Lumpur to histochemically study the mucin profiles of cases of intestinal (IGC) and diffuse (DGC) types of gastric carcinoma in Malaysian patients to determine whether a significant change of mucin type occurs in the event of malignant transformation. 42 IGC and 37 DGC were subjected to alcian blue-periodic acid Schiff and high iron diamine-alcian blue histochemical staining. In addition, 18 cases of gastrectomies performed for benign lesions in the stomach served as normal controls. The number of cases of IGC and DGC which exhibited sulphomucin production was significantly increased (p < 0.001) compared to normal controls. Also, the number of cases of DGC which produced neutral mucin were significantly less (p < 0.05) than the control group. However, there was no significant difference between the number of IGC and DGC cases which demonstrated sialomucin production and normal controls. It appears that while not pathognomonic, a lack of neutral mucin production should alert the pathologist to the possibility of a gastric malignancy, in particular DGC. The likelihood of a malignant lesion would be further supported if there is an increased sulphomucin production.
Fulltext Hydatidiform molar pregnancy in Malaysian women: a histopathological study from the University Hospital, Kuala Lumpur

Cheah PL, Looi LM, Sivanesaratnam V

Malays J Pathol, 1993 Jun;15(1):59-63.
PMID: 8277792

A review of gestational trophoblastic disease diagnosed at the Department of Pathology, University Hospital, Kuala Lumpur from January 1989 to December 1990 using established histological criteria showed 25 complete hydatidiform moles (CHM), 11 partial hydatidiform moles (PHM), 1 invasive mole and 2 choriocarcinoma. The ages of the patients with CHM ranged from 21 to 43 years (mean = 28.5 years) and PHM 20 to 33 years (mean = 27.5 years). The invasive mole occurred in a 42-year-old Malay woman. The two patients with choriocarcinoma were both Chinese and 41 and 46-years old respectively. During the same period, 1,062 non-molar abortions and 13,115 births, inclusive of livebirths and stillbirths were recorded at the University Hospital. The incidence rate of hydatidiform moles was thus estimated to be 1:384 pregnancies. PHM constituted 30% of all molar pregnancies. Hydatidiform moles occurred among the Malays, Chinese and Indians at the rate of 2.43, 2.66 and 3.29 per 1,000 pregnancies respectively. It appears that hydatidiform molar pregnancy has the highest prevalence among the Indians, a finding similar to an earlier Singapore study.
Fulltext In situ hybridisation: principles and applications

Looi LM, Cheah PL

Malays J Pathol, 1992 Dec;14(2):69-76.
PMID: 1304627

In situ hybridisation (ISH) is based on the complementary pairing of labelled DNA or RNA probes with normal or abnormal nucleic acid sequences in intact chromosomes, cells or tissue sections. Compared with other molecular biology techniques applicable to anatomical pathology, ISH enjoys better rapport with histopathologists because of its similarity to immunohistochemistry. It has the unique advantage over other molecular biology techniques--largely based on probe hybridisation with nucleic acid extracted from homogenised tissue samples--of allowing localisation and visualisation of target nucleic acid sequences within morphologically identifiable cells or cellular structures. Probes for ISH may bear radioactive or non-radioactive labels. Isotopic probes (3H, 32P, 35S, 125I) are generally more sensitive than non-isotopic ones but are less stable, require longer processing times and stringent disposal methods. Numerous non-isotopic labels have been used; of these biotin and digoxigenin are the reporters of choice. Optimised non-isotopic systems of equivalent sensitivity to those which use radioactive-labelled probes have been described. In ISH, finding the optimal balance between good morphological preservation of cells and strong hybridisation signals is crucial. Tissue fixation and retention of cytoskeletal structures, unfortunately, impede diffusion of probes into tissues. ISH sensitivity is also influenced by inherent properties of the probe and hybridisation conditions. Although ISH is largely a research tool, it is already making strong inroads into diagnostic histopathology. It has been applied for the detection of various infective agents particularly CMV, HPV, HIV, JC virus, B19 parvovirus, HSV-1, EBV, HBV, hepatitis delta virus, Chlamydia trachomatis, salmonella and mycoplasma in tissue sections.(ABSTRACT TRUNCATED AT 250 WORDS)
Squamous cell carcinoma related antigen in uterine cervical carcinoma

Cheah PL, Yap SF, Looi LM, Sivanesaratnam V

Malays J Pathol, 1991 Jun;13(1):37-41.
PMID: 1795560

Squamous cell carcinoma-related antigen (SCC-Ag), first described by Kato and Torigoe in 1977, has been cited by various workers as a serological marker for some epithelial neoplasms. The most well-studied is its association with carcinoma of the uterine cervix. In January 1989, we embarked on a prospective, multivariate study at the University Hospital, Kuala Lumpur to assess the usefulness of serologically assaying SCC-Ag (using the Abbott RIA diagnostic kit) in our patients with carcinoma of the uterine cervix. We were also interested to ascertain whether SCC-Ag is a 'general' marker for all histological types of cervical carcinoma or specific for squamous carcinoma. From the time of commencement to June 1990, 35 newly-diagnosed and histologically-proven cases were entered into the study. Of these, 4 were keratinising squamous carcinoma, 18 large cell non-keratinising carcinoma, 3 adenosquamous carcinoma, 7 adenocarcinoma and 3 carcinoma-in-situ. Our preliminary results show that all keratinising squamous carcinoma and 1/3 each of large cell non-keratinising carcinoma, adenosquamous carcinoma and carcinoma-in-situ had positive pre-therapy serum SCC-Ag levels (i.e greater than 2 ng/ml, 2 ng/ml being an arbitrarily selected 'cut-off' value). In contrast, no adenocarcinoma was serologically positive. In addition, keratinising squamous carcinoma had the highest mean pre-therapy serum SCC-Ag level. The results imply that serum SCC-Ag is related to the (1) presence of squamous and not glandular differentiation and (2) degree of squamous differentiation.
The pathology of tumour and "tumour-like" lesions of bone in the University Hospital, Kuala Lumpur

Peh SC, Cheah PL, Sengupta S

Malays J Pathol, 1988 Aug;10:45-50.
PMID: 3252076
Screening for microsatellite instability in colorectal carcinoma: Practical utility of immunohistochemistry and PCR with fragment analysis in a diagnostic histopathology setting

Cheah PL, Li J, Looi LM, Koh CC, Lau TP, Chang SW, et al.

Malays J Pathol, 2019 Aug;41(2):91-100.
PMID: 31427545

Since 2014, the National Comprehensive Cancer Network (NCCN) has recommended that colorectal carcinoma (CRC) be universally tested for high microsatellite instability (MSI-H) which is present in 15% of such cancers. Fidelity of resultant microsatellites during DNA replication is contingent upon an intact mismatch repair (MMR) system and lack of fidelity can result in tumourigenesis. Prior to commencing routine screening for MSI-H, we assessed two commonly used methods, immunohistochemical (IHC) determination of loss of MMR gene products viz MLH1, MSH2, MSH6 and PMS2 against PCR amplification and subsequent fragment analysis of microsatellite markers, BAT25, BAT26, D2S123, D5S346 and D17S250 (Bethesda markers) in 73 unselected primary CRC. 15.1% (11/73) were categorized as MSI-H while deficient MMR (dMMR) was detected in 16.4% (12/73). Of the dMMR, 66.7% (8/12) were classified MSI-H, while 33.3% (4/12) were microsatellite stable/low microsatellite instability (MSS/MSI-L). Of the proficient MMR (pMMR), 95.1% (58/61) were MSS/MSI-L and 4.9% (3/61) were MSI-H. The κ value of 0.639 (standard error =0.125; p = 0.000) indicated substantial agreement between detection of loss of DNA mismatch repair using immunohistochemistry and the detection of downstream microsatellite instability using PCR. After consideration of advantages and shortcomings of both methods, it is our opinion that the choice of preferred technique for MSI analysis would depend on the type of laboratory carrying out the testing.
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 Research on cancer diagnosis in Malaysia: current status

Looi LM, Zubaidah Z, Cheah PL, Cheong SK, Gudum HR, Iekhsan O, et al.

Malays J Pathol, 2004 Jun;26(1):13-27.
PMID: 16190103

Cancer is a major morbidity and mortality concern in Malaysia. Based on National Cancer Registry data, the Malaysian population is estimated to bear a cancer burden of about 40,000 new cases per year, and a cumulative lifetime risk of about 1:4. Cancer research in Malaysia has to consider needs relevant to our population, and resources constraints. Hence, funding bodies prioritise cancers of high prevalence, unique to our community and posing specific clinical problems. Cancer diagnosis is crucial to cancer management. While cancer diagnosis research largely aims at improvements in diagnostic information towards more appropriate therapy, it also impacts upon policy development and other areas of cancer management. The scope of cancer diagnosis upon which this paper is based, and their possible impact on other R&D areas, has been broadly categorized into: (1) identification of aetiological agents and their linkages to the development of precancer and cancer (impact on policy development, cancer prevention and treatment), (2) cancer biology and pathogenesis (impact on cancer prevention, treatment strategies and product development), (3) improvements in accuracy, sensitivity and specificity in cancer detection, monitoring and classification (impact on technology development) and (4) prognostic and predictive parameters (impact on treatment strategies). This paper is based on data collected by the Working Group on Cancer Diagnosis Research for the First National Conference on Cancer Research Coordination in April 2004. Data was collated from the databases of Institutions/Universities where the authors are employed, the Ministry of Science, Technology and Innovation (MOSTI) and targeted survey feedback from key cancer researchers. Under the 7th Malaysia Plan, 76 cancer projects were funded through the Intensified Research in Priority Areas (IRPA) scheme of MOSTI, amounting to almost RM15 million of grant money. 47(61.8%) of these projects were substantially in cancer diagnosis, accounting for 65.6% (RM 9.7 million) of cancer project funds. The 8th Malaysia Plan saw a change in research strategy. The IRPA agency fielded several top-down projects which encouraged a multicentre and multidisciplinary approach. This resulted in larger funding per project i.e. RM32 million for 49 projects. There was also a surge of interest in drug development and natural products. Because of this shift in direction, cancer diagnosis projects constituted only 51% of IRPA-funded cancer projects. Nonetheless funding for cancer diagnosis research has exceeded that of the 7th Malaysia Plan, being RM12.5 million by March 2004. The majority of such research is carried out at the Universities, engaging a large number of young scientists and postgraduate students (51 MSc and 21 PhD). A lot of research findings presented at scientific meetings have not yet been published and there is a glaring shortage of patents and commercialization of research findings (such as creation of test kits). Because diagnosis is very much a part of clinical practice, many researchers felt satisfied and confident that their work will be translated into practice and will significantly improve diagnostic services in Malaysia. National guidelines and consensus development on at least three malignancies i.e. breast cancer, oral cancer and lymphoma, have substantial basis in local R&D work. Problems encountered in research included (1) insufficient funding to realize research objectives, (2) lack of local expertise (most research assistants are inexperienced BSc graduates with no or minimal research experience), (3) inadequate technical support from vendors during equipment failure, (4) inexperienced Institutional development units to assist in product development, (5) lack of venture capital for commercialization of findings, and (6) inadequate incentives to undertake research. Researchers pointed out that plans to promote research should include the establishment of (1) regional and national cancer tissue banks, (2) a National Cancer Research Institute, (3) a dedicated cancer research fund, (4) a registry of cancer researchers, (5) national research coordinators, (6) improved coverage by the National Cancer Registry, (7) more international collaboration, (8) a better career structure for researchers, (9) improved Institutional support for product realization, and (10) better recognition for cancer researchers.
Immunohistochemistry usage profile in a Malaysian tertiary hospital's histopathology laboratory

Cheah PL, Chau YT, Looi LM

Malays J Pathol, 2021 Dec;43(3):353-359.
PMID: 34958056

INTRODUCTION: Immunohistochemistry (IHC) was commenced in 1986 at the Department of Pathology, University of Malaya Medical Centre, Kuala Lumpur and its usage has grown for the past 30 over years, hence it was felt that a review was timely in view of the scarcity of literature on IHC usage.
MATERIALS AND METHODS: All cases received by the Department of Pathology for histopathological examination between 1 July 2018 and 30 June 2019 were retrieved from the Laboratory Information System (LIS). All the IHC requests over this period were tabulated, with the exception of renal, muscle, rectal and nerve biopsies with their pre-defined algorithms for stains and cytological specimens. IHC stains performed solely for purpose of directing targeted treatment were also not included.
RESULTS: Immunohistochemistry was performed in 2044 (21.1%) of the total of 9686 cases, with a total of 5969 IHC stains performed i.e. 2.9 (5969/2044) IHC stains per case. All 91 antibodies available were used at least once during the study. 14 histopathologists (5 with < 10-years and 9 with ≥ 10-years postgraduate specialist experience) reported on the cases with no significant difference (p=0.90) in their usage of IHC stains. Among the most common IHC stains used, requests for Ki67 and MNF116 showed higher standard deviations compared with p63, CK7 and S100 among the histopathologists. From the relatively higher standard deviation for Ki67 and MNF116 it appeared that there was a greater difference in the requesting pattern between histopathologists for these two antibodies.
CONCLUSION: The rate of use of IHC in our centre seems compatible with that of an academic centre. Personal preferences of the histopathologists, rather than years of postgraduate specialist experience appeared to influence the rate of usage and choice of antibodies.
ERRATUM: Phyllodes tumours of the breast: retrospective analysis of a University Hospital's experience

Toh YF, Cheah PL, Looi LM, Teoh KH, Tan PH

Malays J Pathol, 2016 08;38(2):175.
PMID: 27568677

No abstract available.

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