Purpose: Invasive micropapillary carcinoma (IMPC) of the breast has a high propensity for lymphovascular invasion and axillary lymph node metastasis and displays an ‘inside-out’ growth pattern, but the molecular mechanism of invasion, metastasis and cell polarity reversal in IMPC is unclear. Methods: and Patients: Cell growth curves, tumor sphere formation assays, transwell assays, mouse xenograft model and immunofluorescence were evaluated to investigate the effects of miR-30c and MTDH. Dual luciferase reporter assays was performed to confirm that the MTDH (metadherin) 3′UTR bound to miR-30c. MiRNA in situ hybridization (ISH) and immunohistochemistry (IHC) were carried out on IMPC patient tissues for miR-30c and MTDH expression, respectively. Results: We found miR-30c as a tumor suppressor gene in cell proliferation, metastasis and polarity reversal of IMPC. Overexpression of miR-30c inhibited cell growth and metastasis in vitro and in vivo. MiR-30c could directly target the MTDH 3′UTR. MiR-30c overexpression inhibited breast cancer cell proliferation, invasion and metastasis by targeting MTDH. Moreover, miR-30c/MTDH axis could also regulate cell polarity reversal of IMPC. By ISH and IHC analyses, miR-30c and MTDH were significantly correlated with tumor size, lymph nodule status and tumor grade, the ‘inside-out’ growth pattern, overall survival (OS) and disease-free survival (DFS) in IMPC patients. Conclusions: Overall, miR-30c/MTDH axis was responsible for tumor proliferation, metastasis and polarity reversal. It may provide promising therapeutic targets and prognostic biomarkers for patients with IMPC.

GATA结合蛋白3(GATA binding protein 3)是一种含锌指结构域的转录因子,GATA3不仅能维持正常乳腺导管腺上皮细胞的生长和分化,并且在多种肿瘤的发生、发展中发挥着重要的作用.目前,有关乳腺癌GATA3的研究正逐步从临床病理特征走向分子机制,其在乳腺癌侵袭和转移中的作用引起广泛关注.GATA3的表达不仅与乳腺癌细胞的增殖、侵袭和转移等生物学行为密切相关,而且与乳腺癌分子分型、临床预后和治疗反应等临床病理学表现息息相关.该文将从分子机制研究和临床病理学表现对涉及GATA3与乳腺癌发生、发展的关系进行综述.

Purpose Invasive micropapillary carcinoma (IMPC) of the breast has a high propensity for lymphovascular invasion and axillary lymph node metastasis and displays an ‘inside-out’ growth pattern, but the molecular mechanism of metastasis and tumor cell polarity reversal in IMPC is unclear. Methods and Patients: Luciferase reporter assays and western blotting were performed to confirm that the MTDH 3’UTR bound to miR-30c. Growth curves, tumor sphere formation assays, Transwell migration and invasion assays, mouse xenograft model and immunofluorescence were evaluated to investigate the effects of miR-30c and MTDH. MiRNA in situ hybridization (ISH) and immunohistochemistry (IHC) were carried out on IMPC patient tissues for miR-30c and MTDH expression, respectively. Results We found that miR-30c could directly target the MTDH (metadherin) 3’UTR. MiR-30c overexpression inhibited breast cancer cell proliferation, invasion and metastasis by targeting MTDH in vitro and in vivo. Moreover, miR-30c regulated IMPC cell polarity reversal by targeting MTDH. By in situ hybridization and immunohistochemistry analyses, miR-30c and MTDH were significantly correlated with tumor size, lymph nodule status and tumor grade, the ‘inside-out’ growth pattern, overall survival (OS) and disease-free survival (DFS) in IMPC patients (p < 0.05). Conclusions Overall, miR-30c overexpression could inhibit breast cancer cell proliferation and metastasis and regulate polarity reversal by targeting MTDH.

Primary hypothyroidism can lead to delayed growth and pseudoprecocious puberty in juvenile patients, which was known as Van Wyk-Grumbach's syndrome (VWGS). There have been very few clinical case reports of primary juvenile hypothyroidism presenting with concurrent huge bilateral cystic ovaries. Here, we report the case of a 14-year-old female patient suffering from primary hypothyroidism in combination with bilateral cystic ovaries. Remarkable improvement of symptoms was observed after one month of hormone replacement therapy and an unnecessary surgical treatment was avoided. A comprehensive literature review of VWGS is summarised here to illustrate the presentation, diagnosis, and treatment of VWGS in pediatric patients. The present study aims to improve the current clinical knowledge of VWGS.

目的:探索上游移码突变体(up-frameshift mutant 1,UPF1)在肺腺癌(adenocarcinoma,ADC)中的表达及其与各临床病理指标的关系,探讨其在临床预后判断中的作用及意义.方法:应用免疫组织化学方法测定2011年1月至2011年12月150例就诊于天津医科大学肿瘤医院ADC患者的UPF1表达情况.Kaplane-Meier分析UPF1的表达与无复发生存期(recurrence-free survival,RFS)以及总生存期(overall survival,OS)之间的关系.结果:UPF1表达水平随ADC恶性程度的增大而降低(P<0.01),也与TNM分期(P=0.014)、是否有淋巴结转移(P=0.016)及远处转移(P=0.035)相关.UPF1的表达水平显著影响ADC的患者RFS和OS,UPF1表达低患者的RFS和OS较短(P<0.05).结论:UPF1在ADC中可能起到抑瘤的作用,可以作为ADC治疗及预后评估的参考指标,并且UPF1有可能成为新的ADC药物治疗靶点.

Despite the development of various treatments, metastasis remains a significant problem with lung adenocarcinoma (ADC). The role and mechanism of epithelial splicing regulatory protein 1 (ESRP1), an epithelial-specific RNA binding protein, on promoting the invasion and metastasis of lung ADC remain to be fully elucidated. Immunohistochemical analysis in 125 human lung ADC tissue samples demonstrated that ESRP1 overexpression was inversely related to the presence of metastases, tumor size, and clinical stage of lung ADC. Impaired ESRP1 expression was also found to stimulate the invasion capacity of lung ADC cells both in vitro and in vivo. Functionally, overexpression of the ZEB1 gene decreased ESRP1 expression, and knockdown of the ZEB1 gene caused increased ESRP1 expression. On the basis of a gene array analysis, the expression of ESRP1 was associated with the regulation of the extracellular matrix. The expression of CD44 and fibroblast growth factor receptor, representatives that interact with the extracellular matrix, was studied. The CD44 subtypes promoted lung ADC cell invasion by regulating matrix metalloproteinase 2 expression. In conclusion, ESRP1 inhibits the invasion and metastasis of lung ADC and plays a role in regulating proteins involved in epithelial-to-mesenchymal transition.

Extragonadal primary yolk sac tumor of the intestinal tract origin is exceedingly rare. Through a multiple disciplinary team, the diagnosis and treatment of primary intestinal yolk sac tumor were further defined. We report 2 such cases with detailed histologic and immunohistochemical analysis. The two patients were a 7-year-old girl and a 29-year-old woman. Both of them preoperatively had an elevated serum alpha fetoprotein（AFP） level（≥ 1,210 ng/mL）. The tumors are located in the intestine and imaging examination indicated the rectum as the primary site. Grossly the mass was grey-white and crisp texture. Microscopic examination featured reticular, microcystic, macrocystic, papillary, solid, and some glandular patterns. Immunohistochemically,tumor cells of both cases were positive for SALL4, AFP, pan-cytokeratin（AE1/AE3）, and glypican-3. Simultaneously, a stain for EMA, OCT4, CD30, HCG, vimentin and CK20 were negative in all 2 neoplasms. The features of morphology,immunohistochemistry, laboratory examinations and imaging studies consist of the diagnosis of primary yolk sac tumor of the intestine.

PURPOSE:Ionizing radiation has been associated with adverse effects on the immune system. Currently, there are no effective treatment options to ameliorate these effects. The aim of the present study was to investigate the protective effects of resveratrol against radiation-induced long-term immunosuppression in mice.MATERIALS AND METHODS:Mice were exposed to total body irradiation and treated with resveratrol or vehicle. Several immune parameters were measured, including thymus and spleen weights, T-lymphocyte and B-lymphocyte count in peripheral blood, concanavalin A and lipopolysaccharide induced lymphocyte proliferation. To explore the mechanism, we investigated intracellular ROS level of lymphocytes and mice plasma cytokine levels.RESULTS:Treatment with resveratrol ameliorated TBI-induced atrophy of the thymus and spleen, reduction of lymphocyte count and decline of lymphocyte proliferation. TBI exhibited significantly reduced level of IL-2, IL-4, IL-7 and IFN-γ compared with the control mice and treatment with resveratrol attenuated the reduction.CONCLUSION:The results of the present study suggest that treatment with resveratrol could ameliorate irradiation induced long-term immune malfunction at least partly via modulation of plasma cytokine.

Invasive micropapillary carcinoma of the breast is a histologic subtype of breast cancer and associated with high incidence of lymphovascular invasion, lymph node metastasis and poor prognosis. The aim of this prospective study was to investigate the impact of precise pathologic diagnosis and individualized treatment on the outcomes of invasive micropapillary carcinoma of the breast. The study group included 2299 women with invasive micropapillary carcinoma diagnosed at Tianjin Medical University Cancer Institute and Hospital between January 2004 and December 2015. In the study group, specimens were examined with the method of whole-specimen orientation and serial sectioning, and patients received precise pathological diagnosis and individualized treatment. The control group of invasive micropapillary carcinoma consisted of 163 cases, identified through a retrospectively review of 9056 invasive carcinomas diagnosed at our institution between January 1989 and December 2003 using the standard pathology-evaluation method (i.e., not using the whole-specimen orientation and serial-sectioning method). The clinicopathological features, treatments and outcomes were compared between the two groups. The incidence of invasive micropapillary carcinoma in the study group was 6% (2299/39,714 cases), significantly higher than that of the control group (2%; 163/9056 cases). The 5-year disease-free survival in the study group was significantly higher than that in the control group (83.8 vs.45.4%; p < 0.05). The 5-year overall survival was significantly increased from 57.4% in the control group to 90.9% in the study group (p < 0.05). In the multivariate analysis, lymphovascular invasion, estrogen receptor status and lymph node metastasis were independent prognostic factors. Although invasive micropapillary carcinoma of the breast is associated with poor prognosis, precise pathologic diagnosis and individualized treatment improved the disease-free survival and overall survival of invasive micropapillary carcinoma patients. Precise pathological diagnosis is the premises for individualized treatments and for improving the outcomes of patients with invasive micropapillary carcinoma of the breast.

OBJECTIVES:The purpose of this study was to distinguish synchronous primary endometrial and ovarian carcinomas from single primary tumor with metastasis by clinical pathologic criteria and whole exome sequencing (WES).MATERIAL AND METHODS:Fifty-two patients with synchronous endometrial and ovarian carcinomas (SEOCs) between 2010 and 2017 were reviewed and subjected to WES.RESULTS:On the basis of the Scully criteria, 11 cases were supposed as synchronous primary endometrial and ovarian carcinomas, 38 cases as single primary tumor with metastasis, and the remaining 3 cases (S50-S52) cannot be defined. Through a quantization scoring analysis, 9 cases that were scored 0-1 point were defined as synchronous primary endometrial and ovarian carcinomas, and 42 cases that were scored 3-8 points were defined as single primary tumor with metastasis. Two of the undefined cases were classified into metastatic disease, and another one that scored 2 points (S52) was subjected to WES. S52 was deemed synchronous primary endometrial and ovarian carcinomas, with few shared somatic mutations and overlapping copy number varieties. The finding of a serous component examined from the uterine endometrium samples further illustrated that the case was synchronous primary endometrial and ovarian carcinomas.CONCLUSION:By scoring criterion, SEOCs were divided into 2 groups: synchronous primary endometrial and ovarian carcinoma group and single primary tumor with metastasis group. The analysis of clonality indicated that the case that scored 2 (S52) can be considered as synchronous primary endometrial and ovarian carcinomas. Scoring criteria of clinical pathology, along with the study of the WES, may further identify the classification of SEOCs.

Background Intestinal injury is a potential cause of death after high-dose radiation exposure. The aim of the present study was to investigate the protective effects of resveratrol against radiation-induced small intestine injury. Methods C57BL/6 N mice were irradiated and treated with resveratrol and/or Ex527 (a potent Sirt1 inhibitor), and subsequent examining intestinal morphological changes, and crypt cell apoptosis. Then, the expression and enzyme activity of SOD2 in the small intestine were examined. Furthermore, Sirt1 and acetylated p53 expression was analysed. Results Compared to the vehicle control, treatment with resveratrol improved intestinal morphology, decreased apoptosis of crypt cells, maintained cell regeneration, and ameliorated SOD2 expression and activity. Resveratrol also regulated Sirt1 and acetylated p53 expression perturbed by irradiation in the small intestine. The protective effect of resveratrol against ionizing radiation induced small intestine injury was significantly inhibited by Ex527. Conclusion Our results suggest that resveratrol decreases the effects of radiation on intestinal injury at least partly via activation of Sirt1.

The Breast JournalVolume 23, Issue 6 p. 764-765 LETTER TO THE EDITOR Comparison of HER2 status of breast cancer between Chinese women in China and Chinese-American women in the US Yi-Ling Yang PhD, Corresponding Author Yi-Ling Yang PhD yyling10@163.com orcid.org/0000-0001-7115-315X Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Cancer Prevention and Therapy (Tianjin), Tianjin Medical University Cancer Institute and Hospital, Tianjin, China National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China Correspondence Yi-Ling Yang, Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. Email: yyling10@163.comSearch for more papers by this authorXiao-Long Qian PhD, Xiao-Long Qian PhD Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Cancer Prevention and Therapy (Tianjin), Tianjin Medical University Cancer Institute and Hospital, Tianjin, China National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, ChinaSearch for more papers by this authorLi Fu PhD, Li Fu PhD Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Cancer Prevention and Therapy (Tianjin), Tianjin Medical University Cancer Institute and Hospital, Tianjin, China National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, ChinaSearch for more papers by this author Yi-Ling Yang PhD, Corresponding Author Yi-Ling Yang PhD yyling10@163.com orcid.org/0000-0001-7115-315X Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Cancer Prevention and Therapy (Tianjin), Tianjin Medical University Cancer Institute and Hospital, Tianjin, China National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China Correspondence Yi-Ling Yang, Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. Email: yyling10@163.comSearch for more papers by this authorXiao-Long Qian PhD, Xiao-Long Qian PhD Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Cancer Prevention and Therapy (Tianjin), Tianjin Medical University Cancer Institute and Hospital, Tianjin, China National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, ChinaSearch for more papers by this authorLi Fu PhD, Li Fu PhD Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Cancer Prevention and Therapy (Tianjin), Tianjin Medical University Cancer Institute and Hospital, Tianjin, China National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, ChinaSearch for more papers by this author First published: 06 September 2017 https://doi.org/10.1111/tbj.12921Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume23, Issue6November/December 2017Pages 764-765 RelatedInformation

Nonsense-mediated mRNA decay (NMD) is a highly conserved pathway that selectively degrades aberrant RNA transcripts. In this study, we proved that NMD regulates the epithelial-mesenchymal transition (EMT) of lung adenocarcinoma (ADC). Moreover, we found that NMD core factor UP-frameshift 1 tends to be expressed at lower levels in human ADC tissues than in normal lung tissues, thereby raising the possibility that NMD may be downregulated to permit ADC oncogenesis. Our experiments in human ADC cell lines showed that downregulating NMD can promote EMT. Moreover, EMT can be inhibited by upregulating NMD. We tested the role of TGF-ß signaling and found that NMD influences EMT by targeting the TGF-ß signaling pathway. Our findings reveal that NMD is a potential tumor regulatory mechanism and may be a potential therapeutic target for ADC.

Invasive micropapillary carcinoma (IMPC) of the breast has distinct histological features and molecular genetic profiles. Gains/amplifications of 8q24 are found associated with IMPC. Although the prostate stem cell antigen (PSCA) gene is located at chromosome 8q24, and found over-expressed in prior studies, its prognostic values and biological significance in IMPC have not been well studied.

Invasive micropapillary carcinoma is a kind of malignant tumor with high risk of invasion and metastasis,which can occur to the breast,lung,bladder and other organs.Because of its high degree of lymphatic invasion,lymph node metastasis and the special histological characteristics of polarity reversal,invasive micropapillary carcinoma (IMPC) gradually attracted the attention of domestic and foreign pathologists and clinicians.In this paper,we reviewed the relationship between the histological features of IMPC and its high risk of invasion and metastasis from the polarity reversal point.

Background: Expression of PD-L1 has been estimated to predict the therapeutic potential of PD-L1 inhibition in solid tumors. Recent studies have demonstrated that PD-L1 plays a critical role in regulatory T-cell (Treg) development and functional maintenance. Although increases in FOXP3+Treg infiltration and PD-L1 expression have been revealed in several malignancies, their correlation in human breast tumors is as yet unclear. Methods: Whole-tissue sections from 501 patients with breast cancer were examined for PD-L1 and FOXP3 expression by immunohistochemistry. Correlation between their expressions and the association with clinicopathological features, intrinsic tumor subtypes and patient's prognosis were studied. Results: PD-L1 expression and FOXP3+Treg infiltrates in tumor tissue demonstrated a high correlation (rs=0.334, p<0.001) in this cohort of breast cancer patients. High PD-L1 expression and increased FOXP3+Treg infiltrates were both associated with high histological grade, negative ER and PR status, and aggressive intrinsic tumor subtypes, especially the basal-like subtype. Tumors with concomitant high expressions of the two markers had the worst prognosis. Multivariate analysis proved both markers to be the independent predictors for decreased overall survival of patients, particularly in the basal-like subtype. Conclusions: The results suggest that PD-L1 and FOXP3+Tregs may work synergistically and their up-regulated expressions promote tumor immune evasion in breast cancer. Combinatorial immunotherapeutic approaches aiming on blocking PD-L1 and depleting Tregs might improve therapeutic efficacy in breast cancer patients, especially those with basal-like carcinoma.

Primary squamous cell carcinoma of breast (PSCCB) is a rare type of breast malignancy that has low hormone receptor expression and poor outcomes. So far no validated prognostic markers for the tumor have been available yet. The purpose of this study is to evaluate its clinicopathologic characteristics, immunohistochemical profile, molecular subtypes, clinical managements and prognosis. Twenty-four cases of PSCCB were identified in the archive of our hospital between January 2003 and October 2014. The medical records and pathologic materials were retrieved and reviewed. The cases accounted for 0.097% of invasive breast carcinoma (total 24666 cases), including 17 cases of pure type and 7 cases of metaplastic type. All patients were female with a median age of 55 years (28 to 87 years). The average tumor size was 4.2 cm (1.2 to 10.0 cm), and axillary lymph node metastasis was identified in 6 out of 20 (30.0%) patients. The most common molecular subtype was basal-like (15 cases). The median OS and DFS were 54 months (6-105 months) and 37 months (5-105 months) respectively. During the follow up, one patient was lost and six patients developed tumor recurrence at chest wall and/or metastasis to bone or lung. On univariate analysis, tumor metastasis to axillary lymph nodes and advanced stage at diagnosis were associated significantly with reduced OS. Tumors with basal-HER2 phenotype seemly have particularly poor prognosis associated with frequent local recurrence and/or distant metastasis. Due to its rarity and lack of ER, PR and HER2 expression in majority of the tumors, treatment of PSCCB is often refractory and remains controversial, although tumors with ER and PR expression may response to hormonal therapy. New therapy regimens, like EGFR tyrosine kinase inhibitors, are currently under active exploration.

Context.-Invasive micropapillary carcinoma (IMPC) is a distinct variant of mammary carcinoma in which tumor cells are arranged in morulelike clusters devoid of fibrovascular cores and situated within empty stromal spaces. Identification of IMPC can be achieved by the assessment of morphologic features in conjunction with the characteristic "inside-out" staining pattern of epithelial membrane antigen and sialyl Lewis X highlighted by immunohistochemical analysis. Although recognizing micropapillary architecture is often not challenging, the criteria for distinguishing between mixed and pure IMPC remain imprecise. Some mucin-producing carcinomas can also have micropapillary histology, but there is no consensus on whether these tumors are variants of IMPC or mucinous carcinomas. The molecular genetic studies demonstrate that IMPCs have distinct molecular genetic profiles, supporting the theory that they constitute distinct pathologic entities. However, genomic analyses have not identified any specific genomic aberration that may explain the distinctive morphology and clinical behavior of IMPC.Objective.-To provide an overview on the current concepts in the diagnosis and pathogenesis of IMPC of the breast, incorporating recent molecular genetic advances and prognosis-based reclassification.Data Sources.-PubMed search and the cited references were reviewed.Conclusions.-The recent evolution of prognosis-based reclassification and molecular genetic advances has enhanced our knowledge of the pathogenesis of IMPC of the breast. Additional studies might reveal consistent molecular alterations that underlie the formation of the inside-out growth pattern, and they might elucidate the molecular mechanisms responsible for the unfavorable clinical behavior of IMPC.

Uterine tumors resembling ovarian sex cord tumor (UTROSCT) is an extremely rare type. It is currently distinguished from endometrial stromal tumors with sex cord-like element (ESTSCLE). We reported four cases recently with UTROSCT to describe the histological morphology, immunophenotype, and clinical behavior. During July, 2014 and Dec, 2015, two patients underwent surgical treatment respectively at Tianjin Medical University Cancer Institute & Hospital and Tianjin Central Hospital of Gynecology Obstetrics, the other two were consultant cases. Hematoxylin & Eosin and Immunohistochemical staining were performed. The sections were reviewed by three independent pathologists to confirm the diagnosis. Four patients with an age range of 35 to 80 years underwent the surgical treatment for UTROSCT. And the biopsy specimen was sent for histopathology and immunohistochemistry. Besides, genes were examined in the two cases, gene fusions of JAZF1-SUZ12 was not detected and FOXL2 gene mutation was also not found. UTROSCTs are polymorphic neoplasms with true sex cord differentiation. Generally, the primary management strategy remains surgical.