The ERK/MAPK pathway is overexpressed and activated in gallbladder cancer

Publication date: Available online 24 February 2017
Source:Pathology - Research and Practice
Author(s): Kurt Buchegger, Ramón Silva, Jaime López, Carmen Ili, Juan Carlos Araya, Pamela Leal, Priscilla Brebi, Ismael Riquelme, Juan Carlos Roa
Gallbladder cancer (GBC) is a highly fatal disease with poor prognosis and few therapeutic alternatives. Molecular profiling has revealed that the deregulation in the ERK/MAPK signaling pathway plays a crucial role in many disease and malignancies, including GBC. The aim of this study was to measure the expression of ERK1/2 and p-ERK1/2 in a population with high GBC-related mortality, such as the Chilean population, and characterize the protein expression of this ERK/MAPK pathway in seven GBC cell lines. Immunohistochemistry (IHC) for ERK1/2 and p-ERK1/2 was performed in 123 GBC tissues and 37 chronic cholecystitis (CC) tissues. In addition, protein expression analysis by western blot for ERK1/2, p-ERK1/2, EGFR, ERBB2 and ERBB3 were performed in seven GBC cell lines (GB-d1, G415, NOZ, OCUG-1, TGBC-1, TGBC-2 and TGBC-24). A higher ERK1/2 and p-ERK1/2 expression was found in GBC tissues compared to chronic cholecystitis (CC) tissues (P<0.001). However, neither significant differences in overall survival nor significant associations with any of the clinicopathological features were found by comparing low and high expression of both ERK1/2 and p-ERK1/2. Western blot analysis of seven GBC cell lines showed that, in general, GB-d1, G415 and NOZ cells evidenced a strong expression of ERK1/2, p-ERK1/2, EGFR, ERBB2 and ERBB3. Therefore, ERK1/2 and p-ERK1/2 seem to be important in the development of GBC and GB-d1, G415 and NOZ cell lines may be used as experimental models for further in vitro and in vivo studies that help to decipher the role of MAPK/ERK pathway in gallbladder carcinogenesis.



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Clear Cell Colorectal Carcinoma: time to clarify diagnosis

Publication date: Available online 24 February 2017
Source:Pathology - Research and Practice
Author(s): Andrea Remo, Federica Grillo, Luca Mastracci, Matteo Fassan, Sokol Sina, Caterina Zanella, Pietro Parcesepe, Emanuele D'Urso, Massimo Pancione, Germana Bortuzzo, Aldo Scarpa, Erminia Manfrin
Primary clear cell colorectal carcinoma (CCC) is a very rare entity accounting for only 35 cases reported in the Literature. CCC is neither classified as a distinct entity nor is it defined as a CRC variant because its ontogeny remains unclear. Most of the reported CCC were found in the distal colon in patients with a mean age of 56 years. Histologically, clear cell change is the main morphologic feature and may present in a "pure" form, composed exclusively of clear cells, or in a "composite" form, admixed with other morphologically different components. It is possible to distinguish two biologically different types of CCC, with different clinical-pathologic features, therapeutic management and diagnostic criteria: a) Intestinal CCC consisting of an aggressive neoplasm, affecting mainly adult men, characterized by an intestinal-type immunoprofile (CK20+, CK7-, CEA+, CDX–2+) and b) Müllerian CCC consisting of an indolent carcinoma of the sigmoid-rectum, affecting young women, characterized by a different (CK7+, CK20-, CEA-, CA125+) immunoprofile. Considerable diagnostic difficulties can arise in distinguishing CCC and primary or secondary clear cell neoplasms, such as metastases from renal carcinoma, lower urinary tract, female genital tract, adrenal gland, mesothelioma, melanoma and primary intestinal PEComa. In this paper we review the Literature with two additional cases in order to define the diagnostic criteria of CCC.



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Prevalence of adeno-associated virus and human papillomavirus DNA in Iranian women with and without cervical cancer

Publication date: Available online 24 February 2017
Source:Pathology - Research and Practice
Author(s): Nazanin Zahra Shafiei-Jandaghi, Jila Yavarian, Ebrahim Faghihloo, Nastaran Ghavami, Zohreh Yousefi ghalejoogh, Seyed Jalal kiani, Somayeh Shatizadeh Malekshahi, Reza Shahsiah, Eisa Jahanzad, Mostafa Hosseini, Talat Mokhtari Azad
There is plenty of substantial evidence to support anti-tumor activity of viruses. Adeno-associated virus (AAV) may interact with human papillomavirus (HPV) to modify the risk of cervical neoplasia. The seroprevalence of AAV among women with cervical cancer has been reported to be lower than healthy ones. In spite of this finding, detection of AAV DNA in cervical biopsies does not entirely support the inverse association between AAV seropositivity and cervical cancer. This association is still controversial and requires more thorough evaluation in different countries. The aim of this case–control study was to find the prevalence of AAV and HPV DNA sequences in Iranian women with and without cervical cancer to assess the probable association of AAV infection and cervical cancer. In this study, paraffin-embedded tissue samples of 61 cervical cancer cases and 50 healthy controls (HCs) were investigated for AAV and HPV DNA by semi-nested and nested PCRs respectively. AAV DNA was detected in 7 cases (14%) of HCs and 9 specimens (14.8%) of case group. According to the branching in the phylogenetic tree, AAV2 was the only type detected in this study. Moreover, HPV DNA was detected in 8 cases (16%) of HCs and 44 specimens (72.13%) of case group. In conclusion, a low proportion of cervical biopsies from Iranian women contained AAV-2 genome. No significant difference in correlation between HPV and cervical cancer in presence or absence of AAV genome in cervix was found.



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Survivin and gynaecological tumours

Publication date: Available online 24 February 2017
Source:Pathology - Research and Practice
Author(s): Dušan Braný, Dana Dvorská, Pavol Slávik, Richard Školka, Marián Adamkov
Survivin is the smallest member of the inhibitors of apoptosis (IAP) family. However, participation in inhibition of apoptosis is not the only function of this molecule. Survivin can also affect the proper process of mitosis and even promoting of angiogenesis or DNA repair. High levels of survivin expression are connected with foetal tissues during intrauterine development. In the overwhelming majority of healthy, differentiated adult tissues, amounts of survivin are markedly reduced. On the other hand, survivin is also often abundantly expressed in cases of various types of cancer. Generally, high expression levels of survivin are associated with a poor prognosis, an increased rate of tumour recurrence and high resistance to chemo- as well as radiotherapy, hence survivin can be considered a factor in the initiation and progression of many types of cancer with great significance and potential for cancer therapy. Nonetheless, progress in development of survivin inhibitors or primarily, in survivin-related molecular therapies, is surprisingly not very fast and indeed remains a challenge for the future. The objective of this article is to summarize known facts about survivin, its contribution to inhibition of apoptosis and cell division and its implication in the development of gynaecological tumours. At the end, known survivin inhibitors and their effect on regulation of tumour growth will be referenced.



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Expression of Vav3 protein and its prognostic value in patients with gastric cancer

Publication date: Available online 24 February 2017
Source:Pathology - Research and Practice
Author(s): Bibo Tan, Yong Li, Xiaoming Shi, Liqiao Fan, Qun Zhao, Yanli Liu, Ming Tan, Qingwei Liu, Nan Jia
Vav3 is associated with tumor growth, apoptosis, invasion, metastasis and angiogenesis. In this study,we detected the expression of Vav3 in gastric cancer tissues, and explored its role in invasion, metastasis and prognosis of gastric cancer. Vav3, MMP-2, MMP-9, TIMP-1 and TIMP-2 in primary lesion and pericarcinous tissues were tested with Immunohistochemistry and Western blot. Results showed a higher expression of Vav3 in primary lesion than in pericarcinous tissue, and the expression of Vav3 was significantly correlated with MMP-2, MMP-9 and TIMP-1 in gastric cancer tissues. Overexpression of Vav3 was associated with poorer differentiation, advanced clinical stage, more significant infiltration depth, lymphatic metastasis, and perineural invasion. Results of Kaplan-Meier verified that overexpression of Vav3 was related to poorer prognosis and shorter survival time. Moreover, Cox proportional hazard model revealed that overexpression of Vav3 was an independent risk factor of prognosis for patients with gastric cancer. In all, we conclude that overexpression of Vav3 is an independent risk factor for prognosis of gastric cancer, and can be used as prognostic indicator. This may be because that Vav3 could regulate genes which associated with the invasion and metastasis.



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Prognostic factors in MNU and DMBA-induced mammary tumors in female rats

Publication date: Available online 24 February 2017
Source:Pathology - Research and Practice
Author(s): Antonieta Alvarado, Ana Lopes, Ana I. Faustino-Rocha, António Cabrita, Rita Ferreira, Paula A. Oliveira, Bruno Colaço
Chemically-induced mammary tumors in rats by the carcinogens 1-metil-1-nitrosurea (MNU) and 7,12-dimetilbenz [a] antracen (DMBA) are the most widely used models for studies related with human breast cancer. This study aimed to evaluate the immunoexpression of the prognostic factors estrogen receptor α (ERα), progesterone receptor (PR) and Ki-67, in MNU and DMBA-induced rat mammary tumors, in order to know the model that best suits to woman breast cancer. Twenty-eight MNU-induced and 16 DMBA-induced mammary tumors in virgin female Sprague-Dawley rats were analyzed. The expression of the prognostic markers ERα, PR and Ki-67 proliferation index (Ki-67 PI) was assessed by immunohistochemistry. Mitotic activity index (MAI) was also evaluated. More than one histological pattern was identified in each mammary tumor. Carcinomas constituted the lesions most frequently induced by both carcinogens: 33 MNU-induced carcinomas and 23 DMBA-induced carcinomas. All MNU and DMBA-induced mammary carcinomas were ER⁺/PR⁺, with a higher expression of ERα when compared with PR. Tumors' weight, the expression of ERα, PR, Ki-67 PI and MAI were higher in MNU-induced mammary carcinomas when compared with the DMBA-induced ones. Statistically significant differences between groups were observed for ERα, PR and MAI (p <0.05). The higher KI-67 PI and MAI in MNU-induced mammary carcinomas are suggestive of a higher aggressiveness of these carcinomas when compared with the DMBA-induced ones, and consequently a worse response to the therapy and a worse prognosis. In this way, the use of the rat model of MNU-induced mammary tumors is advised in experimental protocols aiming to study more aggressive mammary tumors within the group of double-positive mammary tumors (ER⁺/PR⁺).



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Histologic factors predicting invasion in patients with ductal carcinoma in situ (DCIS) in the preoperative core biopsy

Publication date: Available online 24 February 2017
Source:Pathology - Research and Practice
Author(s): Areej M. Al Nemer
BackgroundIt is desirable to decrease the underestimation rate of invasion in cases diagnosed as ductal carcinoma in situ (DCIS) in breast core needle biopsy (CNB) in order to determine the appropriate candidates for axillary staging. The objective of this study is to identify the predictors of invasion in histology.Methods and resultsConsecutive 92 CNB's were retrospectively evaluated. The upstaging rate was 47.8% after surgery. Among all the evaluated parameters, high nuclear grade, single architectural pattern, marked periductal lymphocytic infiltration, partial myoepithelial loss and the presence of foci suspicious of microinvasion were the significant predictors of invasion (two tailed p values 0.0327, 0.0003, 0.0346,<0.0001, 0.0025; respectively). Variables that didn't show significant upstaging include: comedo necrosis, microcalcification, periductal fibrosis, various architectural patterns, tumor attenuation, and the immunophenotype. Previous studies were also reviewed.ConclusionsWe identified 5 predictive factors of upstaging. The lack of standardized quantification method may account, at least partially, for the conflicting results in different studies. To overcome this, we suggested a comprehensive reporting template for DCIS identified in CNB.



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