Stromal CD10 expression and relationship to the E‐cadherin/β‐catenin complex in breast carcinoma

Kim H‐S, Kim G Y, Kim Y W, Park Y‐K, Song J‐Y & Lim S‐J
(2010) Histopathology 56, 708–719
Stromal CD10 expression and relationship to the E‐cadherin/β‐catenin complex in breast carcinoma Aims: Previous investigations have indicated that stromal CD10 expression, and altered levels of both E‐cadherin and β‐catenin, are associated with the biological aggressiveness of human carcinoma. The aim was to evaluate stromal CD10 expression and the association of stromal CD10 with E‐cadherin and β‐catenin in breast carcinoma. Methods and results: The expression of CD10, E‐cadherin and β‐catenin was immunohistochemically analysed in tissue microarrays containing 104 cases of invasive ductal carcinoma (IDC) and 10 cases of ductal carcinoma in situ (DCIS). Stromal CD10 was detected in 49.5% (50/101) of the IDC. No immunoreactivity was identified in the stromal cells of normal breast, DCIS or intraductal components of IDC. Accumulation of the cytoplasmic β‐catenin was found in 87.0% (87/100) of the IDC. Stromal CD10 expression in IDC was significantly correlated with tumour size (P = 0.027), stage (P < 0.001) and histological grade (P = 0.006), the presence of nodal (P = 0.048) and distant (P = 0.015) metastases, oestrogen receptor‐negative status (P = 0.016), cytoplasmic β‐catenin accumulation (P = 0.031) and lower overall survival rate (P = 0.041). Conclusions: Stromal CD10 expression in IDC may constitute an important prognostic marker. Stromal CD10 expression with associated aggressive features might be related to aberrant β‐catenin expression.     

Involvement of α‐ and β‐catenins and E‐cadherin in the development of mammary phyllodes tumours

Tsang J Y S, Mendoza P, Lam C C F, Yu A M C, Putti T C, Karim R Z, Scolyer R A, Lee C S, Tan P H & Tse G M
(2012) Histopathology  61, 667–674 Involvement of α‐ and β‐catenins and E‐cadherin in the development of mammary phyllodes tumours Aims: Phyllodes tumours (PT) are rare but clinically important fibroepithelial tumours of the breast. β‐Catenin, a key component in Wnt signalling, has been shown to be important in the development of PT. It also functions as a component of the cadherin complex, which may therefore be implicated in PT pathogenesis. By assessing stromal α‐catenin, β‐catenin and E‐cadherin expression in 158 PT cases using immunohistochemistry and examining associations with clinicopathological features, we aimed to determine the role of these proteins in PT pathogenesis. Methods and results: Cytoplasmic β‐catenin correlated with α‐catenin expression. A significantly higher expression of both markers was observed in borderline than in benign PT (P = 0.003 and <0.001, respectively), but a lower level was found in malignant PT. Cytoplasmic E‐cadherin expression was significantly higher in borderline and malignant than in benign PT (P = 0.001 and 0.012, respectively), but was not correlated with other markers. Both E‐cadherin and α‐catenin showed stronger correlations with histological parameters than β‐catenin. α‐Catenin showed a significant correlation with recurrence (P = 0.005 and 0.016, respectively). Conclusions: α‐ and β‐catenins may be important in the early stages of PT development, while E‐cadherin may be required for malignant development. The correlation of α‐catenin expression with tumour recurrence may be relevant in predicting PT behaviour.     

β‐Catenin and E‐cadherin expression in stage I adult‐type granulosa cell tumour of the ovary: correlation with tumour morphology and clinical outcome

Aims: To study E‐cadherin and β‐catenin expression in stage I adult‐type granulosa cell tumours (AGCTs) and correlate the findings with tumour morphology and clinical outcome. Methods and results: The study group comprised 62 FIGO stage I AGCTs, including 48 stage IA and 14 stage IC cases. Fifty patients (80.6%) had negative clinical follow‐up over periods from 3.0 to 19.2 years (median 6.4 years), and 12 patients (19.4%) developed metastases at intervals of 3.6–16.2 years (median 8.6 years). β‐Catenin and E‐cadherin were expressed in 62 (100%) and 53 (85%) primary tumours, respectively, and staining was more consistent and intense in areas showing sex cord‐like morphology. In contrast, diffuse tumour areas often showed weak or moderate staining (β‐catenin) or were negative (E‐cadherin), and there was reduced expression of both proteins in luteinized cells. Reduced β‐catenin expression in primary tumours correlated with increased risk of recurrence (P = 0.002) and a shorter time interval to recurrence, whereas there was no correlation between E‐cadherin staining and the risk of metastases. Conclusions: Localized variations in adhesion protein expression may partly explain the diverse morphological patterns exhibited by AGCT, and reduced β‐catenin staining in primary tumours may have value as an adverse prognostic factor.     

Immunohistochemical analysis of the expression of E‐cadherin and ZEB1 in non‐small cell lung cancer

We performed an immunohistochemical analysis of the expression of zinc‐finger E‐box binding homeobox 1 (ZEB1), a master regulator of epithelial‐mesenchymal transition (EMT), and determined its relationship with E‐cadherin in 157 non‐small cell lung carcinomas (93 adenocarcinomas, 36 squamous cell carcinomas, 18 large cell carcinomas, and 10 pleomorphic carcinomas). Although the expression of E‐cadherin was low in the subset of adenocarcinomas (10%) and squamous cell carcinomas (11%), ZEB1 expression was only observed in one case of squamous cell carcinoma and none of the adenocarcinomas. In contrast, the low expression of E‐cadherin (50% and 90%, respectively) and the positive expression of ZEB1 (11% and 50%, respectively) were more frequently observed in poorly differentiated carcinomas (large cell carcinomas and pleomorphic carcinomas). Overall, the expression of ZEB1 was inversely correlated with that of E‐cadherin. Furthermore, the distribution of ZEB1‐positive cancer cells was more restricted than in the area in which the expression of E‐cadherin was lost, and the former was detected within the latter. We concluded that the expression of ZEB1 was not necessarily associated with the low expression of E‐cadherin in lung adenocarcinomas and squamous cell carcinomas. The expression of ZEB1 correlated with an undifferentiated and/or sarcomatoid morphology that may occur in the late stage of EMT.     

Adenoid basal carcinoma combined with invasive squamous cell carcinoma of uterine cervix: A case report of a 37‐year‐old woman and literature review

Adenoid basal carcinoma (ABC) is uncommon malignancy of the uterine cervix and it can be pure or combined with cervical intraepithelial lesions. There were less than 20 cases of ABC combined with invasive squamous carcinoma (mixed type) in English literature. These cases had similar properties as seen at postmenopausal women and diagnosed with abnormal cervical smear findings. Here we present a case of 37‐year‐old woman who suffered from spotting and received endocervical curettage. The pathological report revealed squamous cell carcinoma (SCC) of the cervix. The patient underwent type 3 radical hysterectomy and bilateral pelvic and para‐aortic lymph node dissection. The final pathological report revealed SCC coexisting with ABC. Human papillomavirus (HPV) 16,18 and others (11 types) were negative in both components of the mixed tumor by in situ hybridization detection. Our case was cytokeratin 7 negative, cytokeratin 8 positive and p63 positive which supports the hypothesis that mixed type cervical carcinoma originates from endocervical reserve cells.     

细胞周期素D1和抗原Ki-67在宫颈上皮内瘤样病变和宫颈鳞癌的表达及与人乳头瘤病毒感染转归的关系

目的 研究细胞周期素D1(cyclin D1)、抗原Ki-67在宫颈上皮内瘤样病变(CIN)和宫颈鳞癌发生发展中作用及其与人乳头瘤病毒(HPV)感染转归的关系.方法 2002年1月至2006年12月广州医学院第一附属医院HPV阳性患者104例,分2组:(1)研究组:82例,即病理确诊CIN Ⅰ组17例、CINⅡ组19例、CINⅢ组23例、宫颈鳞癌组23例.(2)对照组:柱状上皮异位22例.应用EnVision法检测宫颈病变组织中cyclin D1、Ki-67蛋白的表达,杂交捕获试验检测宫颈分泌物或阴道残端中HPV感染情况,随访各组患者术后1年内的HPV变化.结果 (1)cyclin D1在各组宫颈组织细胞核内均有表达.其阳性率CINⅢ组[82.61%(19/23)]、宫颈鳞癌组[86.96%(20/23)]与对照组[27.27%(6/22)]、CINⅠ组[58.82%(10/17)]比较,差异有统计学意义(P<0.05),在宫颈鳞癌组与CINⅡ组[68.42%(13/19)]阳性率比较差异有统计学意义(P<0.05).(2)Ki-67在各组宫颈组织细胞核内均有表达,其对照组阳性率[31.82%(7/22)]与CINⅢ组[86.96%(20/23)]、宫颈鳞癌组[91.30%(21/23)]比较差异有统计学意义(P<0.05),而在宫颈鳞癌组与CINⅠ组[58.82%(10/17)]、CIN Ⅱ组[63.16%(12/19)]比较差异有统计学意义(P<0.05).(3)术后1年内各组HPV的转阴率分别与cyclin D1、Ki-67的表达强度呈负相关(rs=-0.299,rs=-0.367,P<0.05).结论 cyclinD1和Ki-67在CIN和宫颈鳞癌的细胞增殖活动中起作用,且两者可能与HPV感染转阴率有关.     

宫颈上皮内瘤变及宫颈鳞癌中cyclin D1、Ki-67的表达及其意义

目的： 检测细胞周期素D1（cyclin D1）、增殖细胞核抗原（Ki-67）在人乳头瘤病毒（HPV）感染患者宫颈上皮内瘤样病变（CIN）及宫颈鳞癌中的表达及其相关性,研究其在CIN及宫颈鳞癌发生及发展过程中的作用。方法: 研究组HPV阳性病理确诊CINⅠ17例、CINⅡ19例、CINⅢ23例、宫颈鳞癌23例,对照组HPV阳性病理确诊柱状上皮异位22例。应用免疫组化S-P法检测宫颈病变组织中cyclin D1、Ki-67蛋白的表达,杂交捕获二代检测宫颈分泌物中HPV感染的情况。结果: (1)Cyclin D1在5组宫颈组织细胞的细胞核内均有表达,CINⅢ组、宫颈鳞癌组与对照组比较差异显著（P<0.05）,CINⅢ组、宫颈鳞癌组与CINⅠ组比较差异显著（P<0.05）,宫颈鳞癌组与CINⅡ组比较差异显著（P<0.05）。(2)Ki-67在5组宫颈组织细胞的细胞核内均有表达,对照组与CINⅢ组比较差异显著（P<0.05）,对照组与宫颈鳞癌组比较差异显著（P<0.05）,CINⅠ组与宫颈鳞癌组比较差异显著（P<0.05）,CINⅡ组与宫颈鳞癌组比较差异显著（P<0.05）。(3)Cyclin D1、Ki-67在CIN及宫颈鳞癌中的表达强度呈正相关关系 （P<0.05）。结论: Cyclin D1和Ki-67在CIN和宫颈鳞癌发生发展及细胞增殖活动中起一定的作用;两者在CIN和宫颈鳞癌的发生发展中可能发挥协同作用。     

Immunohistochemical expression of E‐cadherin in sclerosing adenosis,ductal carcinoma in situ and invasive ductal carcinoma of the breast

E‐cadherin (EC) is an important glycoprotein cell‐adhesion molecule that appears to play a significant role in the progression of breast lesions. The objective of this study was to evaluate EC expression in sclerosing adenosis, ductal carcinoma in situ and invasive ductal carcinoma. Samples of breast lesions from 44 women were used in this study, comprising cases of sclerosing adenosis (n = 11), ductal carcinoma in situ (DCIS) (n = 10) and invasive ductal carcinoma (n = 23). Immunohistochemical evaluation of EC expression was assessed semiquantitatively and considered negative (<10% of cells with stained cytoplasmic membranes), positive+ (10–50% of cells stained) or positive++ (> 50% of cells stained). Fisher's exact test was used to compare the distribution of staining intensity in the lesions (P< 0.05). There was a progressive loss of EC expression from benign to malignant lesions. This difference was statistically significant when sclerosing adenosis was compared with DCIS (P < 0.0002), when sclerosing adenosis was compared with invasive ductal carcinoma (P < 0.008) and when DCIS was compared with invasive ductal carcinoma (P < 0.007). The present findings point to a significant association between reduced EC expression and the progression and aggressivity of breast lesions. Diagn. Cytopathol. 2010. © 2009 Wiley‐Liss, Inc.     

Differences in the ARID‐1 alpha expressions in squamous and adenosquamous carcinomas of uterine cervix

AT‐rich interactive domain 1A (ARID1A) is a tumor suppressor gene involved in chromatin remodeling which encodes ARID1A (BAF250a) protein. Recent studies have shown the loss of ARID1A expression in several types of tumors. This retrospective study was designed to evaluate the differences in tissue expressions of ARID1A in a spectrum of cervical neoplasms. Cervical intraepithelial neoplasms, invasive squamous or adenosquamous carcinomas were identified in 100 patients recently diagnosed as cervical neoplasms based on pathology databases. In this series, there were 29 low‐ and 29 high‐grade cervical intraepithelial neoplasms, 27 squamous cell carcinomas, and 15 adenosquamous carcinomas. Mean age of the patients was 47.8 ± 13 years (20–80 years). It was determined that the expression of ARID1A was statistically significantly down‐regulated in adenosquamous carcinomas when compared with non‐invasive or invasive squamous cell carcinomas (p = 0.015). Lower levels of the ARID1A expression were detected in cases with adenosquamous carcinomas (60%), low‐ or high‐grade squamous intraepithelial lesion (SIL) (31%), and squamous cell carcinomas (18.5%). Our findings have demonstrated the presence of a correlation between ARID1A expression and adenomatous differentiation of uterine squamous cell carcinomas. Therefore, ARID1A gene may suggestively have a role in the pathogenesis of cervical adenosquamous carcinomas.     

Cyclin D1, E‐cadherin and beta‐catenin expression in FIGO Stage IA cervical squamous carcinoma: diagnostic value and evidence for epithelial–mesenchymal transition

Koay M H E, Crook M & Stewart C J R
(2012) Histopathology
Cyclin D1, E‐cadherin and beta‐catenin expression in FIGO Stage IA cervical squamous carcinoma: diagnostic value and evidence for epithelial–mesenchymal transition Aims: Immunohistochemistry is helpful in distinguishing cervical neoplastic lesions from their histological mimics, but has contributed less towards the sometimes problematic distinction of in‐situ and superficially invasive tumours. Epithelial–mesenchymal transition (EMT) may be a mechanism of invasion in cervical neoplasia and expression of EMT‐associated proteins could prove useful in this diagnostic setting. Methods and results: Immunohistochemical expression of cyclin D1, E‐cadherin and beta‐catenin was assessed in 22 biopsy specimens from FIGO Stage IA cervical squamous carcinomas, all of which also included foci of cervical intraepithelial neoplasia (CIN) 3, nine biopsies of CIN 3 adjacent to carcinoma, and 10 cases of CIN 3 only. Most invasive tumour cells expressed cyclin D1 and showed a reduction in E‐cadherin and beta‐catenin staining. Nuclear beta‐catenin expression was not observed. Cyclin D1 staining was reduced or showed altered distribution in most cases of CIN 3, while adhesion protein expression generally was preserved. However, altered protein expression similar to that of invasion was seen in some CIN lesions. Conclusions: Most superficially invasive cervical squamous carcinomas show immunophenotypical changes consistent with EMT. These alterations, particularly cyclin D1 expression, may be useful diagnostically. Similar changes in CIN 3 lesions may indicate the acquisition of increased invasive potential.     

αE‐catenin is a candidate tumor suppressor for the development of E‐cadherin‐expressing lobular‐type breast cancer

Although mutational inactivation of E‐cadherin (CDH1) is the main driver of invasive lobular breast cancer (ILC), approximately 10–15% of all ILCs retain membrane‐localized E‐cadherin despite the presence of an apparent non‐cohesive and invasive lobular growth pattern. Given that ILC is dependent on constitutive actomyosin contraction for tumor development and progression, we used a combination of cell systems and in vivo experiments to investigate the consequences of α‐catenin (CTNNA1) loss in the regulation of anchorage independence of non‐invasive breast carcinoma. We found that inactivating somatic CTNNA1 mutations in human breast cancer correlated with lobular and mixed ducto‐lobular phenotypes. Further, inducible loss of α‐catenin in mouse and human E‐cadherin‐expressing breast cancer cells led to atypical localization of E‐cadherin, a rounded cell morphology, and anoikis resistance. Pharmacological inhibition experiments subsequently revealed that, similar to E‐cadherin‐mutant ILC, anoikis resistance induced by α‐catenin loss was dependent on Rho/Rock‐dependent actomyosin contractility. Finally, using a transplantation‐based conditional mouse model, we demonstrate that inducible inactivation of α‐catenin instigates acquisition of lobular features and invasive behavior. We therefore suggest that α‐catenin represents a bona fide tumor suppressor for the development of lobular‐type breast cancer and as such provides an alternative event to E‐cadherin inactivation, adherens junction (AJ) dysfunction, and subsequent constitutive actomyosin contraction. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

LRIG1 regulates cadherin‐dependent contact inhibition directing epithelial homeostasis and pre‐invasive squamous cell carcinoma development

Epidermal growth factor receptor (EGFR) pathway activation is a frequent event in human carcinomas. Mutations in EGFR itself are, however, rare, and the mechanisms regulating EGFR activation remain elusive. Leucine‐rich immunoglobulin repeats‐1 (LRIG1), an inhibitor of EGFR activity, is one of four genes identified that predict patient survival across solid tumour types including breast, lung, melanoma, glioma, and bladder. We show that deletion of Lrig1 is sufficient to promote murine airway hyperplasia through loss of contact inhibition and that re‐expression of LRIG1 in human lung cancer cells inhibits tumourigenesis. LRIG1 regulation of contact inhibition occurs via ternary complex formation with EGFR and E‐cadherin with downstream modulation of EGFR activity. We find that LRIG1 LOH is frequent across cancers and its loss is an early event in the development of human squamous carcinomas. Our findings imply that the early stages of squamous carcinoma development are driven by a change in amplitude of EGFR signalling governed by the loss of contact inhibition. © 2012 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Differential expression of p16/p21/p27 and cyclin D1/D3, and their relationships to cell proliferation, apoptosis, and tumour progression in invasive ductal carcinoma of the breast

In order to understand the intricate relationship of cell proliferation and apoptosis in tumour development, proliferation markers (Ki-67 and c-myc), apoptosis, cell-cycle inducers cyclin D1 and D3, and cell-cycle inhibitors p16(INK4), p21(CIP1), and p27(KIP1) were evaluated in ductal breast carcinoma. The heterogeneous nature of breast tumours provides a system by which the changes in cell-cycle genes can be explored under a wide range of proliferation and apoptotic indices. To address the above issues, immunohistochemical studies were conducted in 40 pairs of tumours and adjacent normal ductal tissues. The TUNEL method was used to identify apoptotic cells. Except for p27/KIP1, the proliferation (Ki-67, c-myc) and the apoptotic indexes together with levels of p16/INK4a, p21/CIP1, cyclin D1, and cyclin D3, were clearly elevated among tumour tissues, while absent in the adjacent normal tissues. Spearman correlation analysis indicated strong associations among apoptotic index, Ki-67, c-myc, and tumour grade. In addition, p21/CIP1 and cyclin D3 were positively correlated, while p16/INK4a, p27/KIP1, and cyclin D1 were negatively correlated with tumour grade. There was clear decoupling between p21 and p27, as well as decoupling between cyclin D1 and cyclin D3, in terms of their relationship to cell proliferation and apoptosis, indicating differential roles in tumour progression.