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Objective: Considering the clinical evidence of BRAF inhibitors that can treat melanoma patients successfully, we aimed to investigate the status of BRAF mutations of primary mucinous ovarian carcinomas (MOC) in Taiwanese women, and apply the emerging paradigm classification of BRAF mutation groups. Materials and methods: 20 archived primary MOC samples were analyzed. The BRAF mutations of activation segment (exon 15), CR3 (conserved regions 3), kinase domain of the BRAF gene were analyzed using the highly sensitive BRAF mutant enriched kit (FemtoPath®) with Sanger sequencing method. Additionally, we extended our prior reported data of HER2 aberrations and KRAS mutation into this study in order to compare with the status of BRAF mutation. Results: Of them (n = 20), 16 (80%) harbored BRAF missense mutations. Their mutation profile and case number (n) were categorized as (1) class I: V600E (n=1), V600M (n = 1); (2) class II: A598V (n = 1), T599I (n = 10); (3) class III: none (n = 0); and (4) unclassified variants: S602F (n = 2), T599I/S602F (n = 1). The BRAF S602F is novel. The prevalence of BRAF mutation is significantly higher than either HER2 mutation (80% vs. 35%; p = 0.022) or HER2 amplification (80% vs. 35%; p = 0.022). However, the mutation rates of BRAF and KRAS were not significantly different (80% vs. 60%; p = 0.289). Conclusion: Activating BRAF mutation, HER2 amplification, HER2 mutation and KRAS mutation were not mutually exclusive. However, they may even have a synergistic effect in tumorigenesis. BRAF mutation is not uncommon in primary MOC of Taiwanese. The BRAF mutant (T599I) stands the majority. We suggested that there was a lower potential response to the existing V600 BRAF inhibitors, but may be responsive to dual BRAF plus MEK inhibitors or single MEK inhibitor. Further studies are warranted to investigate the clinical benefits of newly targeted therapy in recurrent or advanced stage primary MOC patients carrying different classes of BRAF mutation.

We aimed to compare the assay performance characteristics of HER2 status in mucinous epithelial ovarian cancer (EOC) by ToGA (Trastuzumab for Gastric Cancer) biopsy versus ToGA surgical specimen methods. Forty-nine tissue microarray (TMA) samples of mucinous EOC from Asian women were analyzed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) tests using ToGA trial HER2 scoring methods. The overall concordance between IHC and FISH by the ToGA surgical specimen method is 97.56% and by the ToGA biopsy specimen method is 97.14%. The agreements of HER2 IHC results under both biopsy and surgical specimen methods were nearly perfect (weighted kappa = 0.845). Additionally, the percentage of Her2 FISH amplification showed increasing trend with increasing HER2 IHC ordinals (negative, equivocal, positive) by both TOGA biopsy (P

Hypothesis: Single-nucleotide polymorphisms (SNP) in promoter of human nonmetastatic clone 23 type 1 (nm23-H1) may affect their binding with transcription factors and affect promoter activity as well as gene transcription. Therefore, we investigated the impact of the nm23-H1 gene polymorphisms on the neoplastic lesions of uterine cervix in mid-Taiwan women (women who live in the central area of Taiwan). We expected that women with different genotypes in nm23-H1 polymorphisms, such as rs34214448, rs 16949649, or rs2302254, may have different incidences of cervical neoplasia. Materials and Methods: In total, 366 blood samples were collected from 244 healthy women and 122 patients with cervical neoplasia to analyze 3 nm23-H1 gene single-nucleotide polymorphisms (rs34214448, rs 16949649, and rs2302254). Results: The heterozygous genotypes, TG in rs34214448 or TC in rs 16949649, were differentially distributed between patients with cervical neoplasia and normal women (Hommel adjusted P =.0440 and .0435, respectively) as compared to their homozygotes. Moreover, compared to those with wild-type homozygotes and heterozygotes, women with variant homozygotes TT in rs34214448 or CC in rs 16949649 exert different distributions between patients with cervical neoplasia and normal women (P = .058 and .058). Interestingly, we found the genotype distribution of rs34214448 has significant association with that of rs 16949649 with high consistency. Conclusions: Mid-Taiwan women with the polymorphic heterozygotes TG in rs34214448 or TC in rs 16949649 of human nonmetastatic clone 23 type 1 promoter have the tendency to develop cervical neoplasia while compared to their homozygous counterparts. However, women with variant homozygotes TT in rs34214448 or CC in rs 16949649 exhibit less tendency as compared to those with wild-type homozygotes and heterozygotes. [ABSTRACT FROM AUTHOR]

The choice of appropriate therapeutic plans for primary endocervical adenocarcinomas (ECA) and endometrial adenocarcinomas (EMA) depend on the tumor’s site of origin. The purpose of this study was to compare the performances of the commonly used three-marker (ER/Vim/CEA), four-marker (ER/Vim/CEA/PR) and five-marker (ER/Vim/CEA/PR/p16INK4a) panels in distinguishing between primary ECA and EMA. A tissue microarray was constructed using paraffin-embedded, formalin-fixed tissues from 35 hysterectomy specimens, including 14 ECA and 21 EMA. Utilizing the avidin-biotin (ABC) technique, tissue array sections were immunostained with five commercially available antibodies (ER, Vim, CEA, PR and p16INK4a) to evaluate the performances of their respective three-, four- and five-marker panels in distinguishing between primary ECA and EMA. ER, PR and Vim were more likely to be expressed in EMA, while CEA and p16INK4a were frequently expressed in ECA. The three-marker (ER/Vim/CEA) panel exhibits the most favorable performance in the distinction between these two gynecologic malignancies (ECA vs. EMA). According to our data, when histomorphological and clinical doubt exists as to the primary site of origin, we recommend that the conventional three-marker (ER/Vim/CEA) panel is sufficient, appropriate and useful in distinguishing between primary ECA and EMA, instead of the four-marker (ER/Vim/CEA/PR) and five-marker (ER/Vim/CEA/PR/p16INK4a) panels. Ancillary PR and p16INK4a add no supplementary value to the performance of the conventional three-marker (ER/Vim/CEA) panel. [ABSTRACT FROM AUTHOR]

Gynecological pathologists are used to operating many panels of various markers in combination for the diagnostic distinction between primary endocervical and endometrial adenocarcinomas. The conventional 3-marker (ER/Vim/CEA) panel is the most promising tool. In this study, our aim is to investigate whether a 2-marker panel is enough to distinguish between these two gynecologic malignancies. Additionally, we wish to determine which one is the most favorable among eight panels tested, including six 2-marker (ER/CEA, PR/CEA, Vim/CEA, ER/p16(INK4a), PR/p16(INK4a), Vim/p16(INK4a)) and two 3-marker (ER/Vim/CEA, ER/Vim/p16(INK)) panels. A tissue microarray was constructed using paraffin-embedded, formalin-fixed tissues from 35 hysterectomy specimens, including 14 primary endocervical adenocarcinomas and 21 primary endometrial adenocarcinomas. Utilizing the avidin-biotin complex (ABC) method, tissue array sections were immunostained with five commercially available antibodies (ER, Vim, CEA, PR, and p16(INK4a)) to evaluate their individual frequencies of expression. We found that all eight aforementioned panels showed an encouraging range of overall accuracy (69.2% to 78.3%). However, one panel of 2-markers (Vim, CEA) exhibited the most efficiency (78.3%) in the diagnostic distinction between primary endocervical and endometrial adenocarcinomas. Based on the analyzed data, we conclude that the 2-marker (Vim/CEA) panel seems adequate to be an appropriate, convenient, and efficient means to distinguish between primary endocervical and endometrial adenocarcinomas. Even though there were a limited number of cases, this study still provides valuable references to help avoid wasting resources and unnecessary marker testing. [ABSTRACT FROM AUTHOR]

The choice of appropriate therapeutic plans for primary endocervical adenocarcinomas (ECA) and endometrial adenocarcinomas (EMA) depends on the tumor’s site of origin. Some panels of antibodies help to distinguish primary ECA from EMA. However, unexpected expressions of those markers often exist, which causes this diagnostic dilemma to be still unresolved. In this study, we investigate five commonly used monoclonal antibodies (p53, TTF1, CK7, CK20, and CK34βE12) to evaluate their potential use in distinguishing between these two gynecologic malignancies. A tissue microarray was constructed using paraffin-embedded, formalin-fixed tissues from 35 hysterectomy specimens, including 14 ECA and 21 EMA. Utilizing the avidin–biotin (ABC) technique, tissue array sections were immunostained with the five aforementioned commercially available antibodies. Immunohistochemical (IHC) expressions of p53, TTF1, CK7, CK20, and CK34βE12 were all nonsignificant ( P > 0.05) in frequency differences between the immunostaining results (positive vs. negative) in tumors from both the two primary adenocarcinomas (ECA vs. EMA). It is still uncertain which markers or panels would be the most appropriate for making diagnoses; hence, exploration of other useful markers, which make a definitive distinction between ECA and EMA merits further studies. This study, however, uncovered that the five commonly used monoclonal antibodies (p53, TTF1, CK7, CK20, and CK34βE12) are of no beneficial value in distinguishing between primary ECA and EMA. [ABSTRACT FROM AUTHOR]

Endocervical adenocarcinomas (ECAs) and endometrial adenocarcinomas (EMAs) are malignancies that affect the uterus; however, their biological behaviors are quite different. This distinction has clinical significance because the appropriate therapy may depend on the site of tumor origin. The purpose of this study is to evaluate two different scoring mechanisms of p16INK4a immunohistochemical (IHC) stain in distinguishing between primary ECAs and EMAs. A tissue microarray (TMA) was constructed using formalin-fixed, paraffin-embedded tissue from hysterectomy specimens, including 14 ECAs and 21 EMAs. Tissue array sections were stained with a commercially available antibody, p16INK4a. The avidin–biotin complex method was used to visualize antigens. The staining intensity and extent of the IHC reactions were evaluated using a semi-quantitative scoring system. Two scoring methods were defined on the following bases: (1) independent cytoplasmic staining alone, irrespective of nucleic stain (Method C) and (2) independent nucleic staining alone, irrespective of cytoplasmic staining. (Method N). Of the two scoring mechanisms for p16INK4a expression, Method N showed a significant difference ( P = 0.015), but Method C showed no significant ( P = 0.432) frequency differences in distinguishing between ECAs and EMAs. However, Method N had a higher overall accuracy rate (71.4%) in accurately diagnosing ECAs from EMAs in the total number of p16INK4a IHC cases. According to the data of p16INK4a expression in this TMA study, Method N is favorable and efficient in distinguishing between ECAs and EMAs, while Method C is not. [ABSTRACT FROM AUTHOR]

Background: The goal of our study was to evaluate the influence of genetic polymorphisms of matrix metalloproteinases (MMP)-2, MMP-3 and MMP-7 on susceptibility to endometrial cancer. Methods: In the present study, we enrolled a total of 118 patients with endometrial cancer confirmed by histopathology, and 229 unrelated healthy individuals. Polymorphism for the MMP-2 (rs2285053), MMP-3 (rs3025058) and MMP-7 (rs11568818) genes was genotyped by polymerase chain reaction-restriction enzyme length polymorphism. Results: The frequencies of MMP-7 −181 G/G and A/G genotypes were found to be significantly higher in cancer patients compared with healthy controls (p=0.017). Stratification showed that individuals with MMP-7 −181 G allele were at increased risk for endometrial cancer when >50 years of age [odds ratios (OR)=2.03; 95% confidence interval (CI) 1.21–3.39], endometrioid (OR=1.80; 95% CI 1.11–2.92), low (stage I–II) (OR=1.73; 95% CI 1.05–2.83) or high stage (stage III–IV) (OR=2.69; 95% CI 1.16–6.24). Compared with the A/A genotype, the A/G+G/G genotype modified the risk of developing endometrial carcinoma and significance was detected in patients over 50 years old, and those with endometrioid type and high stage endometrial cancer. However, no significant difference in MMP-2 (-735 C/T) and MMP-3 (6A/5A) genotypes was observed between endometrial carcinoma cases and controls. Conclusions: This is the first report on the association of MMP-2, MMP-3 and MMP-7 gene polymorphisms in endometrial cancer. Our results suggest that individuals with the MMP-7 −181 G/G and A/G genotype may have an increased risk of developing endometrial cancer. Clin Chem Lab Med 2010;48:337–44. [ABSTRACT FROM AUTHOR]

Endocervical adenocarcinomas (ECA) and endometrial adenocarcinomas (EMA) are uterine malignancies that have differing biological behavior. The choice of appropriate therapeutic plan depends indeed on the tumor’s site of origin. In this study, we not only compare the individual expression status of five immunomarkers (ER, PR, Vim, CEA, and p16INK4a), but also evaluate whether p16INK4a adds value to the ER/PR/Vim/CEA panel characteristics in distinguishing between primary ECA and EMA. A tissue microarray (TMA) was constructed using paraffin-embedded, formalin-fixed tissues from 35 hysterectomy specimens, including 14 ECA and 21 EMA. TMA sections were immunostained with five anti-bodies, by avidin–biotin complex (ABC) method for antigen visualization. The staining intensity and area extent of the immunohistochemical (IHC) reactions were appraised by using the semi-quantitative scoring system. The four respective markers (ER, PR, Vim, CEA) and their combined panel expressions showed significant ( p < 0.05) frequency differences between ECA and EMA tumors. The p16INK4a marker also revealed a significant frequency difference ( p < 0.05) between the two sites of origin, but did not demonstrate to have any supplementary value to the 4-marker panel. According to our data, when there is histomorphological and clinical doubt as to the primary site of origin, we recommend that the conventional 4-marker (ER/PR/Vim/CEA) panel is appropriate. Ancillary p16INK4a-marker testing does not add value to the 4-marker panel in distinguishing between primary ECA and EMA. [ABSTRACT FROM AUTHOR]

Objective: Endocervical adenocarcinomas (ECA) and endometrial adenocarcinomas (EMA) are uterine malignancies that have differing biological behaviors. The choice of an appropriate therapeutic plan rests on the tumor's site of origin. In this study, we propose to evaluate whether PR adds value to the performance and test effectiveness of the conventional 3-marker (ER/Vim/ CEA) panel in distinguishing between primary ECA and EMA. Methods: A tissue microarray was constructed using paraffin-embedded, formalin-fixed tissues from 38 hysterectomy specimens, including 14 ECA and 24 EMA. Tissue microarray (TMA) sections were immunostained with 4 antibodies, using the avidin-biotin complex (ABC) method for antigen visualization. The staining intensity and extent of the immunohistochemical (IHC) reactions were appraised using a semi-quantitative scoring system. Results: The three markers (ER, Vim and CEA) and their respective panel expressions showed statistically significant (p < 0.05) frequency differences between ECA and EMA tumors. Although the additional ancillary PR-marker also revealed a significant frequency difference (p < 0.05) between ECA and EMA tumors, it did not demonstrate any supplementary benefit to the 3-marker panel. Conclusion: According to our data, when histomorphological and clinical doubt exists as to the primary site of origin, we recommend that the conventional 3-marker (ER/Vim/CEA) panel is easier, sufficient and appropriate to use in distinguishing between primary ECA and EMA. Although the 4-marker panel containing PR also reveals statistically significant results, the PR-marker offers no supplemental benefit to the pre-existing 3-marker (ER/Vim/CEA) panel in the diagnostic distinction between ECA and EMA. [ABSTRACT FROM AUTHOR]

Background: Endocervical adenocarcinomas (ECAs) and endometrial adenocarcinomas (EMAs) are malignancies that affect uterus; however, their biological behaviors are quite different. This distinction has clinical significance, because the appropriate therapy may depend on the site of tumor origin. The purpose of this study is to evaluate 3 different scoring mechanisms of p16[supINK4a] immunohistochemical (IHC) staining in distinguishing between primary ECAs and EMAs. Methods: A tissue microarray (TMA) was constructed using formalin-fixed, paraffin-embedded tissue from hysterectomy specimens, including 14 ECAs and 24 EMAs. Tissue array sections were immunostained with a commercially available antibody of p16[supINK4a]. Avidin-biotin complex (ABC) method was used for antigens visualization. The staining intensity and area extent of the IHC reactions was evaluated using the semi-quantitative scoring system. The 3 scoring methods were defined on the bases of the following: (1) independent cytoplasmic staining alone (Method C), (2) independent nucleic staining alone (Method N), and (3) mean of the sum of cytoplasmic score plus nucleic score (Method Mean of C plus N). Results: Of the 3 scoring mechanisms for p16[supINK4a] expression, Method N and Method Mean of C plus N showed significant (p-values < 0.05), but Method C showed non-significant (p = 0.245) frequency differences between ECAs and EMAs. In addition, Method Mean of C plus N had the highest overall accuracy rate (81.6%) for diagnostic distinction among these 3 scoring methods. Conclusion: According to the data characteristics and test effectiveness in this study, Method N and Method Mean of C plus N can significantly signal to distinguish between ECAs and EMAs; while Method C cannot do. Method Mean of C plus N is the most promising and favorable means among the three scoring mechanisms. [ABSTRACT FROM AUTHOR]

To correlate matrix metalloproteinase-2 (MMP-2) expression with cervical carcinogenesis, the authors use reverse-transcription polymerase chain reaction to detect MMP-2 mRNA expression in 10 cervical squamous cell carcinoma (SCC), 10 high-grade cervical intraepithelial neoplasia (CIN), and 10 normal tissues. They further detect MMP-2 immunoreactivity of 24 tissue cores in each SCC, high- and low-grade CINs, and a healthy subgroup on a tissue array using integrated optical density (IOD) for number and intensity of stained cells in 345 x 345 pixels. They found the mRNA expression of MMP-2 to be higher in most SSCs (9/10 samples) and high-grade CINs (7/10 samples) but lower in normal tissues. The IOD of MMP-2 was significantly higher in high-grade CIN than in normal and low-grade CIN tissue cores (P < .001 for both) and significantly higher in SCC than in high-grade CIN tissue cores (P < .001). The results show that MMP-2 upregulation confers on tumor cells the ability to degrade the subepithelial basement membrane and subsequently invade the cervix. [ABSTRACT FROM AUTHOR]

The authors investigate the effects of human nonmetastatic clone 23 type 1 (nm223-H1) gene and fungal immunomodulatory protein--Ganoderma tsugae (FIP-gts) on the metastatic potential of cervical cancer cells and assess whether nm23-H1 can influence the action of FIP-gts using cell migration and invasion assays and gelatin zymography. The nm23-H1 gene was stably transfected into Caski cells, which lacked nm23-H1 expression. The results show that nm23-H1 stably transfected Caski cells exhibit reduced cell migration but no change of cell invasion and matrix metalloproteinase (MMP)--2 and --9 activities. FIP-gts reduced cell migration in SiHa and nm23-H1 transfected Caski cells more significantly compared with Caski cells and reduced invasion in Caski and nm23-H1--transfected Caski cells, but it exerted no influence on MMP-2 and MMP-9 activities in them. Conclusively, the nm23-H1 gene suppresses cervical cancer cell migration but not invasion and activities of MMP-2 and MMP-9 and enhances the inhibition of FIP-gts upon migration. [ABSTRACT FROM AUTHOR]

Most of cervical intraepithelial neoplasia 1 (CIN 1) will regress and 12% to 40% of high-grade CIN may progress to squamous cell carcinoma (SCC) of the uterine cervix. However, the differentiation of CIN 1 and high-grade CIN is sometimes controversial among pathologists. Human telomerase reverse transcriptase (hTERT) is therefore applied to detect the differences among normal, CIN 1, high-grade CIN, and SCC tissues of uterine cervix. One hundred six cervical specimens were collected for immunohistochemical study of hTERT. These data were compared with the human papillomavirus (HPV) DNA status. Expression of hTERT in high-grade CIN increased significantly compared to that in CIN 1 (P < .001). A positive relationship was found between high hTERT expression and degree of malignant transformation (P < .001). Most of the cases with high hTERT expression tested positive for the high-risk HPV groups. High hTERT expression was detected in 88.73% of the samples with cervical high-grade CIN or SCC. Low hTERT expression was found in 94.29% of low-grade CIN or normal tissues. Furthermore, 96.92% of the cervical tissues with high hTERT expression were high-grade CIN or SCC. A total of 80.49% of samples with low hTERT expression were low-grade CIN or normal tissues. A significantly increased hTERT expression between CIN 1 and high-grade CIN exhibits a critical progression in cervical carcinogenesis, hTERT can be offered as additional molecular information correlated with more severe dysplasia and SCC. Furthermore, this increased hTERT expression is correlated with high-risk HPVs infection. [ABSTRACT FROM AUTHOR]

We recently reported one interesting case showing mutation-free c-KIT proto-oncogene overexpression and paradoxical hypermethylation in 54 cases of primary squamous cell carcinoma of uterine cervix (SCC). However, its molecular mechanisms still remain unknown. We propose the hypothesis that increased methylation at the CpG islands on the promoter near the first exon region might interfere with the binding of CTCF repressor with c-KIT promoter that regulates c-KIT proto-oncogene expression in such case. Further studies focusing on the status of epigenetic modifications of mutation-free c-KIT (+) tumors are encouraged. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the c-KIT or CD117 gene overexpression in squamous cell carcinoma (SCC) of the uterine cervix.

Jayson GC et al. remarked in Lancet that nearly 100% of mucinous ovarian cancer cases have Kras mutation as well as a high frequency of Her2 amplification. Using the Abbott PathVysion Her2 DNA Probe Kit and Kras mutantenriched PCR Kits (FemtoPath®), 21 samples of primary ovarian mucinous cystadenocarcinomas from Taiwanese patients were examined to determine the status of Her2 amplification and Kras mutations. Our results showed the Her2 amplification rates were 33.33%, while the Kras mutation rates were 61.90%. We present here our results in order to enlighten the readership that the ~100% Kras mutant frequency and the high Her2 amplification rate reported by Jayson et al. may be too exaggerated to be applicable into all populations. Additionally, we report another 2 novel Kras mutations (A11V, V14I). [ABSTRACT FROM AUTHOR]

A letter to the editor in response to the article "Immunohistochemistry: applications to the evaluation of lung pleural neoplasms: part 1," by H. Mani and DS Zander in the November 2012 issue.

A letter to the editor is presented in response to the article "Ewing Sarcoma and Primitive Neuroectodermal Tumor of the Esophagus: Report of a Case and Review of Literature," by A.D. Johnson and colleagues, published in a 2010 issue.

The article presents a study which examines the potential of human epidermal growth factor-like receptor-2 (HER-2) as a therapeutic target in treating primary mucinous epithelial ovarian cancer (EOC). Mucinous and non-mucinous epithelial ovarian cancers were analysed in a tissue microarray study. The results revealed a 100% gene amplification rate of HER2 gene in micinous EOCs, but 0% in non-mucinous EOC.

A letter to the editor is presented discussing the role of anti-cytokeratin CAM 5.2 as a surrogate of the cytokeratin 8/18 monoclonal antibody.

A letter to the editor is presented in response to the article "Occult disseminated tumor cells in lymph nodes of patients with gastric carcinoma. A critical appraisal of assessment and relevance," published in the January 2009 issue.

A letter to the editor is presented in response to the article "Detection of minimal residual disease in blood and bone marrow in early stage breast cancer," by S. Krishnamurthy, M. Cristofanilli, B. Singh, et al in the October 2, 2010 issue.

A letter to the editor is presented in response to the article "Expression of c-MET, low-molecular-weight cytokeratin, matrix metalloproteinases-1 and -2 in spinal chordoma" in the previous issue.

A letter to the editor is presented in response to the article "Malignant Adenomyoepithelioma of the Breast Combined With Invasive Lobular Carcinoma," by Yumi Honda and Ken-ichi Iyama published in the 2009 issue of the journal.

A letter to the editor is presented in response to the article "Pancreatic-type mixed acinar-endocrine carcinoma with alpha-fetoprotein production arising from the stomach: a report of an extremely rare case" in a 2009 issue.