Clinicopathology Significance of p53 and p63 Expression in Indonesian Cervical Squamous Cell Carcinomas

Romus, Ilhami,Triningsih, F.X. Ediati,Mangunsudirdjo, Sagiri,Harijadi, Ahmad Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.12

Background: Human papilloma virus infection is associated with genesis and malignant potential of cervical cancer. E6 and E7 oncogens are known to bind to p53 and retinoblastoma gene products, abrogating their functions as tumor suppressors, leading to an abnormal cell cycle machinery. Roles of the p53 homolog p63 have also been postulated, E6 expression leading to TAp63b degradation allowing anchorage independent growth. Molecular studies correlated with clinicopathological factors are important to determine prognosis and treatment strategies, but results have been controversial and need to be clarified. Aim: To investigate expression of p53 and p63 in cervical squamous cell carcinomas in correlation with age, FIGO staging, morphology, and cancer cell proliferation. Materials and Methods: Expression of p53 and p63 immunohistochemical staining in a total of 56 paraffin-embedded tissues of cervical squamous cell carcinomas from Dr. Sardjito General Hospital Indonesia, was evaluated for correlation with clinicopathological parameters. The Mann-Whitney test was used to compare the percentage of p53 and p63 expression with patient age, FIGO staging and morphology and to compare mean p53 and p63 expression. The Spearman correlation test was applied to correlate p53 and p63 expression with that of Ki-67. A p-value of <0.05 was considered statistically significant. Results: There were significant associations between p53 expression with age (p=0.019) and FIGO staging (p=0.026), but not with with morphology or Ki-67 expression. There were no links between p63 expression and age, morphology, FIGO staging or Ki-67. Conclusions: This study indicated that p53 has a prognostic value in cervical squamous cell carcinomas given the relation with FIGO staging.

p63 Cytoplasmic Aberrance is Associated with High Prostate Cancer Stem Cell Expression

Ferronika, Paranita,Triningsih, F.X. Ediati,Ghozali, Ahmad,Moeljono, Abraham,Rahmayanti, Siti,Shadrina, Arifah Nur,Naim, Awang Emir,Wudexi, Ivan,Arnurisa, Alfa Monica,Nanwani, Sandeep Tarman,Harijadi, Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.5

Introduction: Prostate cancer in Indonesia is the $3^{rd}$ ranking cancer among males and the $5^{th}$ rank for their cancer mortality. Prognostic markers that can identify aggressive prostate cancer in early stages and help select appropriate therapy to finally reduce the mortality are therefore urgently needed. It has been suggested that stem cells in the prostate gland have a role in initiation, progression, and metastasis of cancer, although controversy continues to exist. Maintenance of normal stem cell or reserve cell populations in several epithelia including prostate has been shown to be regulated by p63 and alteration of p63 expression is considered to have an oncogenic role in prostate cancer. We hypothesize that the expression of cytoplasmic aberrance of p63 is associated with high ALDH1A1 expression as a cancer stem cell marker, thus leading to progression of prostate cancer. Methods: Using a cross-sectional study during two years (2009-2010), a total of 79 paraffin embedded tissues of benign prostatic hyperplasia, PIN prostatic intraepithelial neoplasia, low and high Gleason score prostate cancer were investigated using immunohistochemistry. Associations between cytoplasmic p63 and ALDH1A1, as well as with pathological diagnosis, were analyzed by Chi-Square test using SPSS 15.0. Links of both markers with cell proliferation rate (KI-67) and apoptotic rate (cleaved caspase 3) were also analyzed by Kruskal-Wallis test. Results: The mean age of patient at the diagnosis is 70.0 years. Cytoplasmic aberrance of p63 was associated with ALDH1A1 expression (p<0.001) and both were found to have significant relationships with pathological diagnosis (including Gleason score), (p=0.006 and p<0.001 respectively). Moreover, it was also found that higher levels of cytoplasmic p63 were significantly associated with the frequency of proliferating cells and cells undergoing apoptosis in prostate cancers (p=0.001 and p=0.016 respectively). Conclusion: p63 cytoplasmic aberrance is associated with high ALDH1A1 expression. These components are suggested to have an important role in prostate cancer progression and may be used as molecular markers.

Clinicopathological Features of Indonesian Breast Cancers with Different Molecular Subtypes

Widodo, Irianiwati,Dwianingsih, Ery Kus,Triningsih, Ediati,Utoro, Totok,Soeripto, Soeripto Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.15

Background: Breast cancer is a heterogeneous disease with molecular subtypes that have biological distinctness and different behavior. They are classified into luminal A, luminal B, Her-2 and triple negative/basal-like molecular subtypes. Most of breast cancers reported in Indonesia are already large size, with high grade or late stage but the clinicopathological features of different molecular subtypes are still unclear. They need to be better clarified to determine proper treatment and prognosis. Aim: To elaborate the clinicopathological features of molecular subtypes of breast cancers in Indonesian women. Materials and Methods: A retrospective cross-sectional study of 84 paraffin-embedded tissues of breast cancer samples from Dr. Sardjito General Hospital in Central Java, Indonesia was performed. Expression of ER, PR, Her-2 and Ki-67 was analyzed to classify molecular subtypes of breast cancer by immunohistochemistry. The relation of clinicopathological features of breast cancers with molecular subtypes of luminal A, luminal B, Her-2 and triple negative/basal-like were analyzed using Pearson's Chi-Square test. A p-value of <0.05 was considered statistically significant. Results: Case frequency of luminal A, Luminal B, Her-2+ and triple negative/basal-like subtypes were 38.1%, 16.7%, 20.2% and 25%, respectively. Significant difference was found in breast cancer molecular subtypes in regard to age, histological grade, lymph node status and staging. However it showed insignificant result in regard to tumor size. Luminal A subtype of breast cancer was commonly found in >50 years old women (p:0.028), low grade cancer (p:0.09), negative lymph node metastasis (p:0.034) and stage III (p:0.017). Eventhough the difference was insignificant, luminal A subtype breast cancer was mostly found in small size breast cancer (p:0.129). Her-2+ subtype breast cancer was more commonly diagnosed with large size, positive lymph node metastasis and poor grade. Triple negative/basal-like cancer was mostly diagnosed among <50 years old women. Conclusions: This study suggests that immunohistochemistry-based subtyping is essential to classify breast carcinoma into subtypes that vary in clinicopathological features, implying different therapeutic options and prognosis for each subtype.

Malignancy Risk Scoring of Hydatidiform Moles

Pradjatmo, Heru,Dasuki, Djaswadi,Dwianingsih, Ery Kus,Triningsih, Ediati Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.6

Background: Several risk factors leading to malignant transformation of hydatidiform moles have been described previously. Many studies showed that prophylactic chemotherapy for high risk hydatidiform moles could significantly decrease the incidence of malignancy. Thus, it is essential to discover a breakthrough to determine patients with high risk malignancy so that prophylactic chemotherapy can be started as soon as possible. Objectives: Development of a scoring system of risk factors as a predictor of hydatidiform mole malignant transformation. Materials and Methods: This research is a case control study with hydatidiform mole and choriocarcinoma patients as subjects. Multiple logistic regression was used to analyze the data. Odds ratios (OR), attributable at risk (AR : OR-1) and risk index ($ARx{\beta}$) were calculated for develoipment of a scoring system of malignancy risk. The optimal cut-off point was determined using receiver operating characteristic (ROC) curve. Results: This study analyzed 34 choriocarcinoma cases and 68 benign hydatidiform mole cases. Four factors significantly increased the risk of malignancy, namely age ${\geq}35$ years old (OR:4.41, 95%CI:1.07-16.09, risk index 5); gestational age ${\geq}$ 12weeks (OR:11.7, 95%CI:1.8-72.4, risk index 26); uterine size greater than the gestational age (OR:10.2, 95%CI:2.8-36.6, risk index 21); and histopathological grade II-III (OR:3.4, 95%CI:1.1-10.6, risk index 3). The lowest and the highest scores for the risk factors were zero and 55, respectively. The best cut-off point to decide high risk malignancy patients was ${\geq}31$. Conclusions: Malignant transformation of hydatidiform moles can be predicted using the risk scoring by analyzing the above four parameters. Score ${\geq}31$ implies high risk patients so that prophylactic chemotherapy can be promptly administered for prevention.

Clinicopathological Significance of Lymphangiogenesis and Tumor Lymphovascular Invasion in Indonesian Breast Cancers

Widodo, Irianiwati,Ferronika, Paranita,Harijadi, Ahmad,Triningsih, F.X. Ediati,Utoro, Totok,Soeripto, Soeripto Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.2

Background: Lymphangiogenesis, assessed as lymphovascular density (LVD), is the initial step of generalized tumor lymphovascular invasion (LVI). It also involves VEGF-C as the most important protein family. Lymphangiogenesis among breast cancer cases correlations with several clinicopathological factors are important to determine prognosis and treatment strategies, but results have been controversial and require clarification. Aim: To define correlations between VEGF-C expression, LVD and LVI with several clinicopathological parameters from Indonesian breast cancer patients. Materials and Methods: Using a cross-sectional study, a total of 48 paraffin-embedded tissues of breast cancer from Dr. Sardjito General Hospital Indonesia were assessed for VEGF-C expression, LVD and LVI by immunohistochemistry. Correlations of these markers with clinicopathological parameters like patient age, tumor size, lymph node status, grade, ER/PR and Her-2 status, cell proliferation and p-53 expression were investigated by linear analysis. Correlations of VEGF-C expression and LVI with several clinicopathological parameters were analyzed with Coefficient Contingency Chi-Square test. Results: The mean of patients age was 53.0 year, pre and post-menopausal patients accounting for 56.3% and 43.8%, respectively. Some 10.4% were well, 41.7% moderate and 47.9% poorly differentiated. ER positivity was evident in 50% while PR and Her-2 positivity was found in 31.3% and 33.3%, respectively. Breast cancer cells with over-expression of p-53 was 64.6% and with high cell proliferation was 56.3%. Lymph node metastasis was noted in 63.5%, and LVI in 72.9%. Significant correlations were found between LVD and tumor size (p:0.037), grade (p:0.000), lymphnode status (p:0.036), LVI (p:0.003), as well as with p-53 and cell proliferation. There were also significant correlation of VEGF-C (p:0.011) and LVI (p:0.001) with tumor grade. Only ER status was found to have a correlation with tumor size (p:0.027). Conclusions: This study suggested that in Indonesian breast cancer patients, lymphangiogenesis is correlated with tumor size, grade, lymph node status and tumor lymphovascular invasion, the latter also being related with p-53 over expression and high cell proliferation.

Rare Helicobacter pylori Infection May Explain Low Stomach Cancer Incidence: Ecological Observations in Bali, Indonesia

Tanaka, Tsutomu,Mulyadi, I Ketut,Moestikaningsih, Moestikaningsih,Oka, Tjok Gede,Soeripto, Soeripto,Triningsih, FX Ediati,Triyono, Teguh,Heriyanto, Didik Setyo,Hosono, Akihiro,Suzuki, Sadao,Tokudome, Asian Pacific Journal of Cancer Prevention 2016 Asian Pacific journal of cancer prevention Vol.17 No.3

The incidence rate of stomach cancer in Bali, Indonesia, is estimated to be strikingly lower than that in Japan. We conducted an on-site ecological study to investigate the association between the stomach cancer incidence and Helicobacter pylori (H. pylori) infection. Recruiting 291 healthy persons (136 men and 155 women) from the general population in Bali, Indonesia, we conducted a urea breath test (UBT) to examine H. pylori infection, along with a pepsinogen test to detect chronic atrophic gastritis and urine analysis to estimate sodium and potassium excretion. UBT positivities were 9% (2-15, 95% confidence interval) for men and 7% (1-12) for women, and positive cases for H. pylori IgG antibodies were 1% (0-3) for men and 3% (0-5) for women, significantly lower than the respective values in Japan. Positive pepsinogen tests in Bali were 0% (0-0) for men and 1% (0-4) for women, also significantly lower than the Japanese figures. Computed values for daily salt excretion were $13.3{\pm}4.1g$ (mean${\pm}$SD) for men and $11.1{\pm}3.1g$ for women, as high as corresponding Japanese consumption values. Moreover, the estimated potassium excretion was $3.2{\pm}0.7g$ for men and $2.8{\pm}0.6g$ for women in Bali, significantly higher than the figures in Japan. There were no associations across genetic polymorphisms of IL-beta, TNF-alpha, and PTPN11 with UBT positivity. The low incidence of stomach cancer in Bali may thus mainly be due to the rare H. pylori infection. Namely, the bacterium infection seems to be a critical factor for gastric cancer rather than host or other environmental factors.

Association Between HLA-DQ Genotypes and Haplotypes vs Helicobacter pylori Infection in an Indonesian Population

Zhao, Yang,Wang, Jingwen,Tanaka, Tsutomu,Hosono, Akihiro,Ando, Ryosuke,Soeripto, Soeripto,Triningsih, F.X. Ediati,Triono, Tegu,Sumoharjo, Suwignyo,Astuti, E.Y. Wenny,Gunawan, Stephanus,Tokudome, Shink Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.4

Background: Helicobacter pylori is an important gastrointestinal pathogen related to the development of not only atrophic gastritis and peptic ulcer, but also gastric cancer. Human leukocyte antigens (HLA) may play particular roles in host immune responses to bacterial antigens. This study aimed to investigate the association between HLA-DQA1 and DQB1 genotypes and haplotypes vs H. pylori infection in an Indonesian population. Methods: We selected 294 healthy participants in Mataram, Lombok Island, Indonesia. H. pylori infection was determined by urea breath test (UBT). We analyzed HLA-DQA1 and DQB1 genotypes by PCR-RFLP and constructed haplotypes of HLA-DQA1 and DQB1 genes. Multiple comparisons were conducted according to the Bonferroni method. Results: The H. pylori infection rate was 11.2% in this Indonesian population. The DQB1*0401 genotype was noted to be associated with a high risk of H. pylori infection, compared with the DQB1*0301 genotype. None of the HLA-DQA1 or DQB1 haplotypes were related to the risk of H. pylori infection. Conclusions: The study suggests that HLADQB1 genes play important roles in H. pylori infection, but there was no statistically significant association between HLA-DQA1 or DQB1 haplotypes and H.pylori infection in our Lombok Indonesian population.

The Polymerase Chain Reaction in Diagnosis of Small B-Cell Non-Hodgkin Lymphomas

Antoro, Ester Lianawati,Dwianingsih, Ery Kus,Indrawati, Indrawati,Triningsih, FX Ediati,Harijadi, Harijadi Asian Pacific Journal of Cancer Prevention 2016 Asian Pacific journal of cancer prevention Vol.17 No.2

Background: Small B-cell non-Hodgkins lymphoma (NHL) is difficult to be distinguished from non-neoplastic reactive processes using conventional haematoxylin-eosin (HE) staining due to different interpretations among pathologists with diagnosis based on morphologic features. Ancillary examinations such as immunohistochemical (IHC) staining are essential. However, negative or doubtful results are still sometimes obtained due to unsatisfactory tissue processing or IHC technique. The polymerase chain reaction (PCR) as a molecular diagnostic technique is very sensitive and specific. Clonality detection of heavy chain immunoglobulin (IgH) gene rearrangement has been widely used to establish diagnosis of B-cell NHL. Aims: To elaborate interobserver variation in small B-cell NHL diagnosis based on morphologic features only and to confirm sensitivity and specificity of the PCR technique as an ancillary method. Materials and Methods: A toptal of 28 samples of small B cell NHL and suspicious lymphoma were interpreted by 3 pathologists in Sardjito General Hospital based on their morphology only. The reliability of assessment and the coefficient of interobserver agreement were calculated by Fleiss kappa statistics. Interpretation results were confirmed with IHC staining (CD20, CD3, Bcl2). PCR was performed to analyze the clonality of IgH gene rearrangement. Results: Interobserver agreement in morphologic evalution of small B cell NHL and chronic lymphadenitis revealed kappa coefficient 0.69 included in the substantial agreement category. The cases were divided into 3 groups based on morphology and IHC results; lymphoma, reactive process and undetermined group. PCR analysis showed 90% sensitivity and 60% specificity. Conclusions: The present study revealed a substantial agreement among pathologists in small B-cell NHL diagnosis. For difficult cases, PCR is useful as complementary method to morphologic and IHC examinations to establish definitive diagnosis.

Histopathological Features of Lymphoma in Yogyakarta, Indonesia

Dwianingsih, Ery Kus,Indrawati, Indrawati,Hardianti, Mardiah Suci,Malueka, Rusdy Ghazali,Iswar, Riezka Rivani,Sutapa, Stefani APPG,Triningsih, FX Ediati Asian Pacific Journal of Cancer Prevention 2016 Asian Pacific journal of cancer prevention Vol.17 No.9

The incidence and prevalence, the second most common lymphoid malignancy after leukemia, are both increasing. The distribution of lymphoma varies among sexes, age groups, and sites. In Indonesia, information about the incidence of lymphoma and its characteristics are insufficient. Therefore, this study was performed to evaluate the incidence of lymphoma and features based on age group, sex, site, clinical diagnosis, and histopathological type in Indonesia. This study is an observational analytical study with a cross-sectional design aimed to evaluate the histopathological profile of lymphoma in Yogyakarta from 2010-2014. It was based on secondary data from Anatomic Pathology Department's medical records from several hospitals and laboratories. The result showed an increased incidence of lymphoma in Yogyakarta in 2010-2014 (p=0.039). Lymphoma mostly occurred in age range 45-64 years (p=0.004), dominated by male with ratio 1.6:1. DLBCL was found to be the most common histopathological type (44.4%). Sex, age, and clinical diagnosis demonstrated statistically significant correlations with the histopathological type (p<0.001). In conclusion, the incidence of lymphoma has significantly increased from 2010-2014. There are statistically significant correlations between gender, age, and clinical diagnosis with the histopathological type of lymphoma.