Clustering of HR + /HER2- breast cancer in an Asian cohort is driven by immune phenotypes.

Breast cancer exhibits significant heterogeneity, manifesting in various subtypes that are critical in guiding treatment decisions. This study aimed to investigate the existence of distinct subtypes of breast cancer within the Asian population, by analysing the transcriptomic profiles of 934 breast cancer patients from a Malaysian cohort. Our findings reveal that the HR + /HER2- breast cancer samples display a distinct clustering pattern based on immune phenotypes, rather than conforming to the conventional luminal A-luminal B paradigm previously reported in breast cancers from women of European descent. This suggests that the activation of the immune system may play a more important role in Asian HR + /HER2- breast cancer than has been previously recognized. Analysis of somatic mutations by whole exome sequencing showed that counter-intuitively, the cluster of HR + /HER2- samples exhibiting higher immune scores was associated with lower tumour mutational burden, lower homologous recombination deficiency scores, and fewer copy number aberrations, implicating the involvement of non-canonical tumour immune pathways. Further investigations are warranted to determine the underlying mechanisms of these pathways, with the potential to develop innovative immunotherapeutic approaches tailored to this specific patient population.

Access to pathology and laboratory medicine services: a crucial gap.

As global efforts accelerate to implement the Sustainable Development Goals and, in particular, universal health coverage, access to high-quality and timely pathology and laboratory medicine (PALM) services will be needed to support health-care systems that are tasked with achieving these goals. This access will be most challenging to achieve in low-income and middle-income countries (LMICs), which have a disproportionately large share of the global burden of disease but a disproportionately low share of global health-care resources, particularly PALM services. In this first in a Series of three papers on PALM in LMICs, we describe the crucial and central roles of PALM services in the accurate diagnosis and detection of disease, informing prognosis and guiding treatment, contributing to disease screening, public health surveillance and disease registries, and supporting medical-legal systems. We also describe how, even though data are sparse, these services are of both insufficient scope and inadequate quality to play their key role in health-care systems in LMICs. Lastly, we identify four key barriers to the provision of optimal PALM services in resource-limited settings: insufficient human resources or workforce capacity, inadequate education and training, inadequate infrastructure, and insufficient quality, standards, and accreditation.

Delivering modern, high-quality, affordable pathology and laboratory medicine to low-income and middle-income countries: a call to action.

Modern, affordable pathology and laboratory medicine (PALM) systems are essential to achieve the 2030 Sustainable Development Goals for health in low-income and middle-income countries (LMICs). In this last in a Series of three papers about PALM in LMICs, we discuss the policy environment and emphasise three crucial high-level actions that are needed to deliver universal health coverage. First, nations need national strategic laboratory plans; second, these plans require adequate financing for implementation; and last, pathologists themselves need to take on leadership roles to advocate for the centrality of PALM to achieve the Sustainable Development Goals for health. The national strategic laboratory plan should deliver a tiered, networked laboratory system as a central element. Appropriate financing should be provided, at a level of at least 4% of health expenditure. Financing of new technologies such as molecular diagnostics is challenging for LMICs, even though many of these tests are cost-effective. Point-of-care testing can substantially reduce test-reporting time, but this benefit must be balanced with higher costs. Our research analysis highlights a considerable deficiency in advocacy for PALM; pathologists have been invisible in national and international health discourse and leadership. Embedding PALM in LMICs can only be achieved if pathologists advocate for these services, and undertake leadership roles, both nationally and internationally. We articulate eight key recommendations to address the current barriers identified in this Series and issue a call to action for all stakeholders to come together in a global alliance to ensure the effective provision of PALM services in resource-limited settings.

Improving pathology and laboratory medicine in low-income and middle-income countries: roadmap to solutions.

Insufficient awareness of the centrality of pathology and laboratory medicine (PALM) to a functioning health-care system at policy and governmental level, with the resultant inadequate investment, has meant that efforts to enhance PALM in low-income and middle-income countries have been local, fragmented, and mostly unsustainable. Responding to the four major barriers in PALM service delivery that were identified in the first paper of this Series (workforce, infrastructure, education and training, and quality assurance), this second paper identifies potential solutions that can be applied in low-income and middle-income countries (LMICs). Increasing and retaining a quality PALM workforce requires access to mentorship and continuing professional development, task sharing, and the development of short-term visitor programmes. Opportunities to enhance the training of pathologists and allied PALM personnel by increasing and improving education provision must be explored and implemented. PALM infrastructure must be strengthened by addressing supply chain barriers, and ensuring laboratory information systems are in place. New technologies, including telepathology and point-of-care testing, can have a substantial role in PALM service delivery, if used appropriately. We emphasise the crucial importance of maintaining PALM quality and posit that all laboratories in LMICs should participate in quality assurance and accreditation programmes. A potential role for public-private partnerships in filling PALM services gaps should also be investigated. Finally, to deliver these solutions and ensure equitable access to essential services in LMICs, we propose a PALM package focused on these countries, integrated within a nationally tiered laboratory system, as part of an overarching national laboratory strategic plan.

Universal health coverage and intersectoral action for health: key messages from Disease Control Priorities, 3rd edition.

The World Bank is publishing nine volumes of Disease Control Priorities, 3rd edition (DCP3) between 2015 and 2018. Volume 9, Improving Health and Reducing Poverty, summarises the main messages from all the volumes and contains cross-cutting analyses. This Review draws on all nine volumes to convey conclusions. The analysis in DCP3 is built around 21 essential packages that were developed in the nine volumes. Each essential package addresses the concerns of a major professional community (eg, child health or surgery) and contains a mix of intersectoral policies and health-sector interventions. 71 intersectoral prevention policies were identified in total, 29 of which are priorities for early introduction. Interventions within the health sector were grouped onto five platforms (population based, community level, health centre, first-level hospital, and referral hospital). DCP3 defines a model concept of essential universal health coverage (EUHC) with 218 interventions that provides a starting point for country-specific analysis of priorities. Assuming steady-state implementation by 2030, EUHC in lower-middle-income countries would reduce premature deaths by an estimated 4·2 million per year. Estimated total costs prove substantial: about 9·1% of (current) gross national income (GNI) in low-income countries and 5·2% of GNI in lower-middle-income countries. Financing provision of continuing intervention against chronic conditions accounts for about half of estimated incremental costs. For lower-middle-income countries, the mortality reduction from implementing the EUHC can only reach about half the mortality reduction in non-communicable diseases called for by the Sustainable Development Goals. Full achievement will require increased investment or sustained intersectoral action, and actions by finance ministries to tax smoking and polluting emissions and to reduce or eliminate (often large) subsidies on fossil fuels appear of central importance. DCP3 is intended to be a model starting point for analyses at the country level, but country-specific cost structures, epidemiological needs, and national priorities will generally lead to definitions of EUHC that differ from country to country and from the model in this Review. DCP3 is particularly relevant as achievement of EUHC relies increasingly on greater domestic finance, with global developmental assistance in health focusing more on global public goods. In addition to assessing effects on mortality, DCP3 looked at outcomes of EUHC not encompassed by the disability-adjusted life-year metric and related cost-effectiveness analyses. The other objectives included financial protection (potentially better provided upstream by keeping people out of the hospital rather than downstream by paying their hospital bills for them), stillbirths averted, palliative care, contraception, and child physical and intellectual growth. The first 1000 days after conception are highly important for child development, but the next 7000 days are likewise important and often neglected.

Scientific misconduct encountered by APAME journals: an online survey.

In June 2015, invitations were sent by email to 151 APAME journals to participate in an online survey with an objective of gaining insight into the common publication misconduct encountered by APAME editors. The survey, conducted through SurveyMonkey over a 20-day-period, comprised 10 questions with expansions to allow anecdotes limited to 400 characters, estimated to take less than 10 minutes to complete. Only one invitation was issued per journal, targeting (in order of priority) editors, editorial board members and editorial staff, and limited by email availability. 54 (36%) journals responded. 98% of respondents held Editor or Editorial Board positions. All respondent journals have editorial policies on publication ethics and 96% provide instructions related to ethics. 45% use anti-plagiarism software to screen manuscripts, the most popular being iThenticate, CrossCheck and Turnitin. Up to 50% of journals had encountered studies without IRB approval. Author misconduct encountered were (in rank order): plagiarism (75%), duplicate publication (58%), unjustified authorship (39%), authorship disputes (33%), data falsification (29%), data/image manipulation (27%), conflict of interest (25%), copyright violation (17%) and breach of confidentiality (10%). Reviewer misconduct encountered were: conflict of interest (19%), plagiarism (17%), obstructive behavior (17%), abusive language (13%) and breach of confidentiality (13%). Notwithstanding the limitations of the survey and the response rate, a few insights have been gained: (1) the need for strengthening the ethical culture of researchers/authors and reviewers, (2) anti-plagiarism software can improve plagiarism detection by about 15%, and (3) the need for technical support to detect plagiarism, duplicate publication and image manipulation.

A comparison of 1995 WHO classification with 2003 ISN/RPS classification of lupus nephritis: a single centre observation.

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.

E-cadherin downregulation at the infiltrating tumour front is associated with histological grade and stage in colorectal carcinoma of Malaysians.

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.

Superficial acral fibromyxoma: insights from case management and comprehensive literature review.

Superficial acral fibromyxoma, also known as digital fibromyxoma, is a slow-growing, benign, solitary soft tissue tumor. First described in 2001 by Fetsch et al., it is a condition that often occurs in middle-aged individuals. However, it has also been reported across a wide range of ages, ranging from 4 to 86 years, with males more commonly reported. The condition often presents as solitary soft tissue swelling over the periungual or subungual. We present the management experience of the rare presentation of this rare tumor and a detailed review of the past literature on this condition. Detailed management of the condition has been described, along with the outcome after 2 years of follow-up and treatment experience. Our detailed analysis shows that 2 years is the shortest duration of follow-up to rule out recurrence. Hence, most of the cases reported earlier had given the false sense of the recurrence rate of the tumor, which could lead to undertreatment of the condition. The purpose of this article is to allow the readers to understand better the tumor's characteristics with bone involvement and the tumor's diagnostic strategies and treatment options.

Gene expression signature for predicting homologous recombination deficiency in triple-negative breast cancer.

Triple-negative breast cancers (TNBCs) are a subset of breast cancers that have remained difficult to treat. A proportion of TNBCs arising in non-carriers of BRCA pathogenic variants have genomic features that are similar to BRCA carriers and may also benefit from PARP inhibitor treatment. Using genomic data from 129 TNBC samples from the Malaysian Breast Cancer (MyBrCa) cohort, we developed a gene expression-based machine learning classifier for homologous recombination deficiency (HRD) in TNBCs. The classifier identified samples with HRD mutational signature at an AUROC of 0.93 in MyBrCa validation datasets and 0.84 in TCGA TNBCs. Additionally, the classifier strongly segregated HRD-associated genomic features in TNBCs from TCGA, METABRIC, and ICGC. Thus, our gene expression classifier may identify triple-negative breast cancer patients with homologous recombination deficiency, suggesting an alternative method to identify individuals who may benefit from treatment with PARP inhibitors or platinum chemotherapy.

Triple-negative breast cancer and PTEN (phosphatase and tensin homologue) loss are predictors of BRCA1 germline mutations in women with early-onset and familial breast cancer, but not in women with isolated late-onset breast cancer.

INTRODUCTION: Given that breast cancers in germline BRCA1 carriers are predominantly estrogen-negative and triple-negative, it has been suggested that women diagnosed with triple-negative breast cancer (TNBC) younger than 50 years should be offered BRCA1 testing, regardless of family cancer characteristics. However, the predictive value of triple-negative breast cancer, when taken in the context of personal and family cancer characteristics, is unknown. The aim of this study was to determine whether TNBC is a predictor of germline BRCA1 mutations, in the context of multiple predictive factors. METHODS: Germline mutations in BRCA1 and BRCA2 were analyzed by Sanger sequencing and multiple ligation-dependent probe amplification (MLPA) analysis in 431 women from the Malaysian Breast Cancer Genetic Study, including 110 women with TNBC. Logistic regression was used to identify and to estimate the predictive strength of major determinants. Estrogen receptor (ER) and phosphatase and tensin homologue (PTEN) status were assessed and included in a modified Manchester scoring method. RESULTS: Our study in an Asian series of TNBC patients demonstrated that 27 (24.5%) of 110 patients have germline mutations in BRCA1 (23 of 110) and BRCA2 (four of 110). We found that among women diagnosed with breast cancer aged 36 to 50 years but with no family history of breast or ovarian cancer, the prevalence of BRCA1 and BRCA2 mutations was similar in TNBC (8.5%) and non-TNBC patients (6.7%). By contrast, in women diagnosed with breast cancer, younger than 35 years, with no family history of these cancers, and in women with a family history of breast cancer, the prevalence of mutations was higher in TNBC compared with non-TNBC (28.0% and 9.9%; P = 0.045; and 42.1% and 14.2%; P < 0.0001, respectively]. Finally, we found that incorporation of estrogen-receptor and TNBC status improves the sensitivity of the Manchester Scoring method (42.9% to 64.3%), and furthermore, incorporation of PTEN status further improves sensitivity (42.9% to 85.7%). CONCLUSIONS: We found that TNBC is an important criterion for highlighting women who may benefit from genetic testing, but that this may be most useful for women with early-onset breast cancer (35 years or younger) or with a family history of cancers. Furthermore, addition of TNBC and PTEN status improves the sensitivity of the Manchester scoring method and may be particularly important in the Asian context, where risk-assessment models underestimate the number of mutation carriers.

Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients.

INTRODUCTION: Germline TP53 mutations cause an increased risk to early-onset breast cancer in Li-Fraumeni syndrome (LFS) families and the majority of carriers identified through breast cancer cohorts have LFS or Li-Fraumeni-like (LFL) features. However, in Asia and in many low resource settings, it is challenging to obtain accurate family history and we, therefore, sought to determine whether the presence of early-onset breast cancer is an appropriate selection criteria for germline TP53 testing. METHODS: A total of 100 patients with early-onset breast cancer (≤ 35 years) treated at University Malaya Medical Centre between 2003 and 2009, were analyzed for germline mutations in BRCA1, BRCA2 and TP53 by full DNA sequencing. Of the mutations identified, we examined their likely pathogenicity on the basis of prevalence in a case-control cohort, co-segregation analyses and loss of heterozygosity (LOH) in tumor tissues. RESULTS: We identified 11 BRCA1 (11%) and 6 BRCA2 (6%) germline carriers among early-onset breast cancer patients. Of the 83 BRCA-negative patients, we identified four exonic variants and three intronic variants in TP53. Of these, two exonic variants are clinically relevant (E346X and p. G334_R335dup6) and two novel missense mutations (A138V and E285K) are likely to be clinically relevant, on the basis of co-segregation and loss of heterozygosity (LOH). Notably, E285K was found in two unrelated individuals and haplotype analyses suggest a founder effect. Two of the three intronic variants are likely benign based on their prevalence in a control population. Clinically relevant TP53 germline mutations were identified in three of the four patients (75%) with a family history of at least two LFS-linked cancers (breast, bone or soft tissue sarcoma, brain tumors or adrenocortical cancer); 1 of the 17 patients (6%) with a family history of breast cancer only, and 1 of the 62 patients (< 2%) with no family history of breast or LFS-linked cancers. CONCLUSIONS: Our study reports germline BRCA1, BRCA2 and TP53 mutations are found in early-onset breast cancer patients at 11%, 6% and 5% respectively, suggesting that TP53 mutation screening should be considered for these patients. However, we find that even in low resource Asian settings where family history is poorly reported, germline TP53 mutations are found predominantly among breast cancer patients with a family history of LFS-linked cancers.

Clinical predictors of non-diabetic renal disease and role of renal biopsy in diabetic patients with renal involvement: a single centre review.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is reportedly the leading cause of end-stage renal disease (ESRD) worldwide. However, non-diabetic renal diseases (NDRD) are not uncommon among T2DM patients with renal involvement. Our study aimed to examine the prevalence of NDRD in T2DM and clinical markers for diabetic nephropathy (DN) and NDRD and to determine the role of renal biopsy in T2DM patients and its impact on clinical practice. METHODS: We conducted a retrospective analysis of T2DM patients in whom renal biopsies were performed from January 2004 to March 2008 (n = 110). RESULTS: Biopsy results were divided into three groups: group I/pure DN (62.7%), group II/isolated NDRD (18.2%), and group III/mixed lesions (19.1%). The causes of NDRD in decreasing order of frequency were acute interstitial nephritis, glomerulonephritides, hypertensive renal disease, and acute tubular necrosis. Significant clinical markers for DN are presence of diabetic retinopathy and longer duration of diabetes. For NDRD, useful clinical markers include the presence of acute renal failure and microscopic hematuria. In the DN subgroup, Indians had significantly shorter duration of diabetes on biopsy compared with Malays and Chinese. CONCLUSIONS: NDRD is prevalent in T2DM patients, and given its potentially treatable nature, renal biopsy should be considered in T2DM patients with nephropathy, especially in those with atypical features.

Silicone Breast Implant Rupture From Pectoralis Muscle Contraction Causing IgA Nephropathy: A Case Report.

A 34-year-old woman who was diagnosed with a left breast carcinoma underwent breast conserving surgery and axillary dissection. This was followed with adjuvant breast irradiation and endocrine therapy. She had a local recurrence in the breast 7 years later. She underwent a left nipple sparing mastectomy and submuscular implant reconstruction. The silicone implant ruptured during an episode of strong pectoralis muscle contraction, 5 years postimplantation. MRI confirmed the rupture to be intracapsular and extracapsular. She declined implant replacement. She presented with painless hematuria 2.5 years after the rupture. A renal biopsy confirmed IgA nephropathy.

Propylthiouracil-Induced Antineutrophil Cytoplasmic Antibodies-Associated Vasculitis with Renal and Lung Involvement.

Propylthiouracil (PTU)-induced antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) is a rare and heterogeneous disease. Moreover, optimal treatment is still lacking. We described the case of a 44-year-old lady with underlying Graves' disease who had cough, blood-streaked sputum, and impaired renal function. A strongly positive anti-myeloperoxidase antibody (>200 U/mL) along with pauci-immune glomerulonephritis and pulmonary hemorrhage resulted in the diagnosis of PTU-induced AAV, given that the patient had been on PTU for 3 years. PTU withdrawal, therapeutic plasma exchanges, and oral cyclophosphamide provided favorable clinical and biochemical outcomes. She remained well on azathioprine 50 mg daily as maintenance therapy and clinically euthyroid with carbimazole 2.5 mg daily. The effective treatment for drug-induced ANCA vasculitis remains controversial, but rapid withdrawal of the offending medication should be the mainstay of treatment. In severe drug-induced ANCA vasculitis with pulmonary hemorrhage and/or life-threatening organ involvement such as kidney failure requiring dialysis, therapeutic plasma exchange with immunosuppressants is often required. In this case, we have shown that patient achieved remission after therapeutic plasma exchange with cyclophosphamide in the acute stage of treatment and remained symptom-free with azathioprine in the maintenance phase of treatment for 24 months.

Allred Scoring of ER-IHC Stained Whole-Slide Images for Hormone Receptor Status in Breast Carcinoma.

Hormone receptor status is determined primarily to identify breast cancer patients who may benefit from hormonal therapy. The current clinical practice for the testing using either Allred score or H-score is still based on laborious manual counting and estimation of the amount and intensity of positively stained cancer cells in immunohistochemistry (IHC)-stained slides. This work integrates cell detection and classification workflow for breast carcinoma estrogen receptor (ER)-IHC-stained images and presents an automated evaluation system. The system first detects all cells within the specific regions and classifies them into negatively, weakly, moderately, and strongly stained, followed by Allred scoring for ER status evaluation. The generated Allred score relies heavily on accurate cell detection and classification and is compared against pathologists' manual estimation. Experiments on 40 whole-slide images show 82.5% agreement on hormonal treatment recommendation, which we believe could be further improved with an advanced learning model and enhancement to address the cases with 0% ER status. This promising system can automate the exhaustive exercise to provide fast and reliable assistance to pathologists and medical personnel. The system has the potential to improve the overall standards of prognostic reporting for cancer patients, benefiting pathologists, patients, and also the public at large.

Human papillomavirus in cervical cancers of Malaysians.

AIM: With cervical carcinoma remaining the second leading cancer among Malaysian women, it is imperative to clarify the prevalence of human papillomavirus (HPV) in this respect, considering the dearth of local information. MATERIAL AND METHODS: Formalin-fixed, paraffin-embedded (FP) tissues of 29 invasive cervical carcinoma cases, diagnosed between 1 January 1991 and 31 December 1992, fresh, frozen (FF) and paired FP tissues of 43 cases diagnosed between 1 January 1995 and 31 December 2000, and 21 FF normal control cervices were subjected to polymerase chain amplification (PCR) for HPV following successful amplification of a 268 bp ß-globin fragment using primers specific for HPV types 6, 11, 16 and 18 and consensus L1 ORF (MY09/11). RESULTS: HPV was detected in 69.0% of the cases diagnosed in the earlier, 88.4% of those in the later period and 4.8% of the normal control cervices. HPV 16 formed 80.0% of the HPV types in the earlier and 55.3% in the later period, while HPV 18 formed 5% in the earlier and 13.2% in the later. HPV 16 was more common in squamous (56.4%) than adeno/adenosquamous carcinomas (35.3%), while HPV 18 was detected in 17.6% of adeno/adenosquamous and 5.5% squamous carcinomas. CONCLUSION: HPV prevalence in invasive cervical carcinoma of Malaysians is similar to that observed worldwide. Together, HPV 16 and 18 constituted 85% of the HPV types responsible for cervical carcinogenesis in Malaysians in the earlier and 68% in the later period. Thus, the use of current vaccines should lower cervical carcinoma rate significantly.

Implications of continued upregulation of p16(INK4a) through the evolution from high-grade squamous intraepithelial lesion to invasive squamous carcinoma of the cervix.

On integration into the host cervical keratinocyte genome, human papillomavirus (HPV) E7 protein binds pRB,releasing E2F from normally incompetent pRB-E2F complexes and allowing propagation of G1-S transition by the E2F. p16(INK4a), a tumour suppressor protein, increases in reflex response to counter this. 29 histologically re-confirmed low-grade squamous intraepithelial lesions (LSIL), 27 high-grade squamous intraepithelial lesions (HSIL) and 30 invasive cervical squamous carcinoma (SCC) were immunohistochemically stained for p16(INK4a) expression using the CINtec Histology Kit (REF 9511, mtm laboratories AG, Heidelberg, Germany) to re-affirm the notion that integration of HPV occurs predominantly in SCC and possibly HSIL and less in LSIL and normal squamous epithelium (NSqE). Implicit was also the attempt to understand the role of E2F, as indicated by p16(INK4a), in evolution of SCC from HSIL. No ethnic predilection was noted for LSIL, HSIL or SCC. Patients with SCC were significantly older by about 14-years compared with HSIL (p < 0.05) while there was no significant age difference between HSIL and LSIL. p16(INK4a) expression was significantly increased (p < 0.05) in both HSIL (88.9%) and SCC (83.3%) compared with LSIL (3.4%) and NSqE (0%); the NSqE being normal squamous epithelium noted in 17 of the LSIL, 19 HSIL and 5 SCC. From these findings there is suggestion that fundamental upstream events viz HPV integration, E7 upregulation followed by E2F activation occurs at point of transformation to HSIL and continues unrelentingly for another one to two decades before hitherto unclear factors convert a non-invasive lesion into an overtly invasive malignant counterpart. Interestingly, the occurrence of HSIL and LSIL in almost the same age group could mean that alteration from episomal to integrated form of HPV may not incur a prolonged incubation period, unlike from HSIL to SCC.