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Shioya A, Takata M, Kumagai M, Hoshi D, Han J, Oyama T, Haba Y, Morioka E, Inokuchi M, Noguchi M, Yamada S. Periarterial or perivenous invasion is an independent indicator of lymph node metastasis in invasive breast carcinoma of no special type. Pathol Res Pract 2024; 260:155407. [PMID: 38936093 DOI: 10.1016/j.prp.2024.155407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 06/05/2024] [Accepted: 06/12/2024] [Indexed: 06/29/2024]
Abstract
Pathological diagnosis of breast cancer often includes cases of lymph node metastases without lymphatic or lymphovascular invasion by the primary tumor. In this study, to resolve this discrepancy, we designed a sensitive method to detect lymphatic invasion and correlate it with lymph node metastasis. Elastica van Gieson (EVG) staining and D2-40 immunohistochemistry revealed the abundant distribution of lymphatic vessels around blood vessels in the mammary tissue in close proximity to the elastic fibers around the arteries and veins. Based on the histological location of the blood and lymphatic vessels, we hypothesized that, in breast cancer, perivascular invasion is similar to lymphatic invasion and correlates with the presence of lymph node metastasis. Using EVG staining, perivascular invasion was histologically classified into periarterial invasion (periA), perivenous invasion (periV), and periarterial or perivenous invasion (periA/V). We tested our method and compared it to other methods commonly used for identifying lymphatic invasion in 105 patients with invasive breast carcinoma of no special type (IBC-NST) who received minimal preoperative therapy. The correlation between perivascular invasion and lymph node metastasis in these patients was statistically analyzed, including findings related to lymphatic invasion, such as retractile artifacts and perineural invasion. PeriA, periV, and periA/V showed significant correlations with lymph node metastasis. PeriA/V had high sensitivity and negative predictive value. The odds ratio (OR) for periV was significantly high in the univariate analysis, while the ORs for periA/V, retraction artifacts, and perineural invasion were significantly high in both the univariate and multivariate analyses. In particular, periA/V revealed a strong correlation with lymph node metastasis (OR: 61.8). These findings indicate that the IBC-NST periA/V ratio is a sensitive pointer of lymphatic invasion and could be an independent and reliable indicator of lymph node metastasis.
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Affiliation(s)
- Akihiro Shioya
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, Japan.
| | - Mao Takata
- Department of Pathology, Kanazawa Medical University Hospital, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, Japan
| | - Motona Kumagai
- Department of Pathophysiological and Experimental Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, Japan
| | - Daisuke Hoshi
- Department of Oncologic Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, Japan
| | - Jia Han
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, Japan
| | - Takeru Oyama
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, Japan
| | - Yusuke Haba
- Department of Breast and Endocrine Surgery, Breast Center, Kanazawa Medical University Hospital, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, Japan
| | - Emi Morioka
- Department of Breast and Endocrine Surgery, Breast Center, Kanazawa Medical University Hospital, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, Japan
| | - Masafumi Inokuchi
- Department of Breast and Endocrine Surgery, Breast Center, Kanazawa Medical University Hospital, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, Japan
| | - Masakuni Noguchi
- Department of Breast and Endocrine Surgery, Breast Center, Kanazawa Medical University Hospital, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, Japan
| | - Sohsuke Yamada
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, Japan
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Senchukova MA, Kalinin EA, Volchenko NN. Different types of tumor microvessels in stage I-IIIA squamous cell lung cancer and their clinical significance. World J Clin Oncol 2024; 15:614-634. [PMID: 38835849 PMCID: PMC11145955 DOI: 10.5306/wjco.v15.i5.614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/12/2024] [Accepted: 03/28/2024] [Indexed: 05/21/2024] Open
Abstract
BACKGROUND Lung cancer (LC) is the leading cause of morbidity and mortality among malignant neoplasms. Improving the diagnosis and treatment of LC remains an urgent task of modern oncology. Previously, we established that in gastric, breast and cervical cancer, tumor microvessels (MVs) differ in morphology and have different prognostic significance. The connection between different types of tumor MVs and the progression of LC is not well understood. AIM To evaluate the morphological features and clinical significance of tumor MVs in lung squamous cell carcinoma (LUSC). METHODS A single-center retrospective cohort study examined medical records and archival paraffin blocks of 62 and 180 patients with stage I-IIIA LUSC in the training and main cohorts, respectively. All patients underwent radical surgery (R0) at the Orenburg Regional Cancer Clinic from May/20/2009 to December/14/2021. Tumor sections were routinely processed, and routine Mayer's hematoxylin and eosin staining and immunohistochemical staining for cluster of differentiation 34 (CD34), podoplanin, Snail and hypoxia-inducible factor-1 alpha were performed. The morphological features of different types of tumor MVs, tumor parenchyma and stroma were studied according to clinicopathological characteristics and LUSC prognosis. Statistical analysis was performed using Statistica 10.0 software. Univariate and multivariate logistic regression analyses were performed to identify potential risk factors for LUSC metastasis to regional lymph nodes (RLNs) and disease recurrence. Receiver operating characteristic curves were constructed to discriminate between patients with and without metastases in RLNs and those with and without disease recurrence. The effectiveness of the predictive models was assessed by the area under the curve. Survival was analyzed using the Kaplan-Meier method. The log-rank test was used to compare survival curves between patient subgroups. A value of P < 0.05 was considered to indicate statistical significance. RESULTS Depending on the morphology, we classified tumor vessels into the following types: normal MVs, dilated capillaries (DCs), atypical DCs, DCs with weak expression of CD34, "contact-type" DCs, structures with partial endothelial linings, capillaries in the tumor solid component and lymphatic vessels in lymphoid and polymorphocellular infiltrates. We also evaluated the presence of loose, fine fibrous connective tissue (LFFCT) and retraction clefts in the tumor stroma, tumor spread into the alveolar air spaces (AASs) and fragmentation of the tumor solid component. According to multivariate analysis, the independent predictors of LUSC metastasis in RLNs were central tumor location (P < 0.00001), the presence of retraction clefts (P = 0.003), capillaries in the tumor solid component (P = 0.023) and fragmentation in the tumor solid component (P = 0.009), whereas the independent predictors of LUSC recurrence were tumor grade 3 (G3) (P = 0.001), stage N2 (P = 0.016), the presence of LFFCT in the tumor stroma (P < 0.00001), fragmentation of the tumor solid component (P = 0.0001), and the absence of tumor spread through the AASs (P = 0.0083). CONCLUSION The results obtained confirm the correctness of our previously proposed classification of different types of tumor vessels and may contribute to improving the diagnosis and treatment of LUSC.
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Affiliation(s)
- Marina A Senchukova
- Department of Oncology, Orenburg State Medical University, Orenburg 460000, Russia
| | - Evgeniy A Kalinin
- Department of Thoracic Surgery, Orenburg Regional Cancer Clinic, Orenburg 460021, Russia
| | - Nadezhda N Volchenko
- Department of Pathology, PA Hertzen Moscow Oncology Research Centre, Branch of National Medical Research Radiological Center, Moscow 125284, Russia
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Seibel AJ, Kelly OM, Dance YW, Nelson CM, Tien J. Role of Lymphatic Endothelium in Vascular Escape of Engineered Human Breast Microtumors. Cell Mol Bioeng 2022; 15:553-569. [PMID: 36531861 PMCID: PMC9751254 DOI: 10.1007/s12195-022-00745-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 10/06/2022] [Indexed: 11/09/2022] Open
Abstract
Introduction Lymphatic vasculature provides a route for metastasis to secondary sites in the body. The role of the lymphatic endothelium in mediating the entry of breast cancer cells into the vasculature remains unclear. Methods In this study, we formed aggregates of MDA-MB-231 human breast carcinoma cells next to human microvascular lymphatic endothelial cell (LEC)-lined cavities in type I collagen gels to model breast microtumors and lymphatic vessels, respectively. We tracked invasion and escape of breast microtumors into engineered lymphatics or empty cavities under matched flow rates for up to sixteen days. Results After coming into contact with a lymphatic vessel, tumor cells escape by moving between the endothelium and the collagen wall, between endothelial cells, and/or into the endothelial lumen. Over time, tumor cells replace the LECs within the vessel wall and create regions devoid of endothelium. The presence of lymphatic endothelium slows breast tumor invasion and escape, and addition of LEC-conditioned medium to tumors is sufficient to reproduce nearly all of these inhibitory effects. Conclusions This work sheds light on the interactions between breast cancer cells and lymphatic endothelium during vascular escape and reveals an inhibitory role for the lymphatic endothelium in breast tumor invasion and escape. Supplementary Information The online version contains supplementary material available at 10.1007/s12195-022-00745-9.
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Affiliation(s)
- Alex J. Seibel
- Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA 02215 USA
| | - Owen M. Kelly
- Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA 02215 USA
| | - Yoseph W. Dance
- Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA 02215 USA
| | - Celeste M. Nelson
- Department of Chemical and Biological Engineering, Princeton University, 303 Hoyt Laboratory, 25 William Street, Princeton, NJ 08544 USA
- Department of Molecular Biology, Princeton University, Princeton, NJ USA
| | - Joe Tien
- Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA 02215 USA
- Division of Materials Science and Engineering, Boston University, Boston, MA USA
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Lv J, Shi Q, Han Y, Li W, Liu H, Zhang J, Niu C, Gao G, Fu Y, Zhi R, Wu K, Li S, Gu F, Fu L. Spatial transcriptomics reveals gene expression characteristics in invasive micropapillary carcinoma of the breast. Cell Death Dis 2021; 12:1095. [PMID: 34799559 PMCID: PMC8605000 DOI: 10.1038/s41419-021-04380-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 10/26/2021] [Accepted: 10/29/2021] [Indexed: 11/09/2022]
Abstract
Invasive micropapillary carcinoma (IMPC) is a special histological subtype of breast cancer, featured with extremely high rates of lymphovascular invasion and lymph node metastasis. Based on a previous series of studies, our team proposed the hypothesis of "clustered metastasis of IMPC tumor cells". However, the transcriptomics characteristics underlying its metastasis are unknown, especially in spatial transcriptomics (ST). In this paper, we perform ST sequencing on four freshly frozen IMPC samples. We draw the transcriptomic maps of IMPC for the first time and reveal its extensive heterogeneity, associated with metabolic reprogramming. We also find that IMPC subpopulations with abnormal metabolism are arranged in different spatial areas, and higher levels of lipid metabolism are observed in all IMPC hierarchical clusters. Moreover, we find that the stromal regions show varieties of gene expression programs, and this difference depends on their distance from IMPC regions. Furthermore, a total of seven IMPC hierarchical clusters of four samples share a common higher expression level of the SREBF1 gene. Immunohistochemistry results further show that high SREBF1 protein expression is associated with lymph node metastasis and poor survival in IMPC patients. Together, these findings provide a valuable resource for exploring the inter- and intra-tumoral heterogeneity of IMPC and identify a new marker, SREBF1, which may facilitate accurate diagnosis and treatment of this disease.
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Affiliation(s)
- Jianke Lv
- Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
- National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Qianqian Shi
- Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
- National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Yunwei Han
- Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
- National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Weidong Li
- Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
- National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Hanjiao Liu
- Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
- National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Jingyue Zhang
- Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
- National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Chen Niu
- Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
- National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Guangshen Gao
- Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
- National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Yiru Fu
- Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
- National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Renyong Zhi
- Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
- National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Kailiang Wu
- Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
- National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Shuai Li
- Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
- National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Feng Gu
- Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
- National Clinical Research Center of Cancer, Tianjin, 300060, China.
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China.
| | - Li Fu
- Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
- National Clinical Research Center of Cancer, Tianjin, 300060, China.
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China.
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Huang L, Li Y, Du J, Li H, Lu M, Wang Y, Zhou W, Wang W, Wu H. The Prognostic Value of Retraction Clefts in Chinese Invasive Breast Cancer Patients. Pathol Oncol Res 2021; 27:1609743. [PMID: 34257612 PMCID: PMC8262209 DOI: 10.3389/pore.2021.1609743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 03/25/2021] [Indexed: 11/13/2022]
Abstract
Some studies reported the correlation between retraction clefts (RCs) and the clinicopathological features as well as prognosis in invasive breast carcinoma. However, limited number of investigations have been done and controversial results were reported. Larger population studies around the world might help to provide more accurate and comprehensive information. Thus, we examined the correlation between the extent of RCs and the clinicopathological features as well as the prognosis in 541 invasive breast carcinoma samples from Central China in this study. The statistical analyses were performed with the Pearson χ2 tests and univariate Cox proportional hazards regression assays. Compared with other studies, lower RCs occurrence rate (15.5%) was observed in Chinese breast cancer patients and opposite association between the presence of RCs and lymph nodes metastasis was identified, in which both progression free survival (PFS) and overall survival (OS) were improved with the presence of RCs in our study. Besides, despite some statistically significant associations between RCs and molecular subtypes, RCs and estrogen receptor status, the results were largely depending on the stratification methods. Generally, no convincing association was detected between the extent of RCs and the clinicopathological features or prognosis. In sum, the extent of RCs showed limited value as a prognostic predictor in invasive breast carcinoma patients from Central China.
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Affiliation(s)
- Liangliang Huang
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yujie Li
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Jun Du
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Heng Li
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Mengmeng Lu
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yuting Wang
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Wenchao Zhou
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Wei Wang
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Haibo Wu
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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Manola I, Mataic A, Drvar DL, Pezelj I, Dzombeta TR, Kruslin B. Peritumoral Clefting and Expression of MMP-2 and MMP-9 in Basal Cell Carcinoma of the Skin. In Vivo 2021; 34:1271-1275. [PMID: 32354918 DOI: 10.21873/invivo.11901] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 03/17/2020] [Accepted: 03/18/2020] [Indexed: 11/10/2022]
Abstract
BACKGROUND/AIM Peritumoral clefting is one of the main histologic features of basal cell carcinoma of the skin (BCC). The aim of the study was to analyze the expression of MMP-2 and MMP-9 both in cells of basal cell carcinoma and in the adjacent stroma and to correlate the findings of immunohistochemical analysis with the presence of peritumoral clefting. PATIENTS AND METHODS The study was made on archival material comprising 48 cases of BCC. These were scanned for the presence of peritumoral clefts. The results of immunohistochemical staining for MMP-2 and MMP-9 were determined semiquantitatively using immunohistochemical staining index (ISI). RESULTS Peritumoral retractions were found in 40 BCC cases. Positive immunohistochemical reaction for MMP-2 in tumor cells was found in 47 cases and in all cases in the adjacent stroma. Positive immunostaining for MMP-9 in BCC tumor cells was observed in 37 cases and in all cases in the adjacent stroma. There was no statistically significant association between peritumoral retractions and expression of MMPs. A statistically significant correlation was found in the expression of both MMP-2 and MMP-9 between the tumor and the stroma. CONCLUSION Tumor cells elaborate MMP-2 and -9, but they also produce some other factors that may induce production of MMPs in adjacent stromal cells. The role of MMPs in the development of peritumoral clefts could not be confirmed.
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Affiliation(s)
| | - Ana Mataic
- Clinical Department of Pathology and Cytology, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Daniela Ledic Drvar
- School of Medicine, University of Zagreb, Zagreb, Croatia.,Department of Dermatology and Venereology, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Ivan Pezelj
- Department of Urology, University Hospital Centre "Sestre milosrdnice", Zagreb, Croatia
| | - Tihana Regovic Dzombeta
- School of Medicine, University of Zagreb, Zagreb, Croatia.,Clinical Department of Pathology and Cytology "Ljudevit Jurak", University Hospital Centre "Sestre milosrdnice", Zagreb, Croatia
| | - Bozo Kruslin
- School of Medicine, University of Zagreb, Zagreb, Croatia .,Clinical Department of Pathology and Cytology "Ljudevit Jurak", University Hospital Centre "Sestre milosrdnice", Zagreb, Croatia
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Agarwal S, Singh A, Bagga PK. Immunohistochemical evaluation of lymphovascular invasion in carcinoma breast with CD34 and D2-40 and its correlation with other prognostic markers. INDIAN J PATHOL MICR 2018; 61:39-44. [PMID: 29567882 DOI: 10.4103/ijpm.ijpm_791_16] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Background Carcinoma breast is ever-evolving and becoming increasingly prevalent in India. Numerous prognostic factors based on morphology and immunohistochemistry (IHC) have been established which need to be interconnected to give patients best possible treatment. Aims This study aims to confirm and analyze lymphovascular invasion (LVI) detected by hematoxylin and eosin (H and E) using IHC with CD34 and D2-40 and its correlation with other biologic and morphologic prognostic markers. Settings and Design This was a prospective study. Materials and Methods Fifty mastectomy specimens diagnosed as infiltrating ductal carcinoma breast on histopathology selected for the study. Evaluation of formalin-fixed paraffin-embedded sections was done using H and E and IHC for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 HER2/neu receptors, CD34, and D2-40 endothelial markers. Correlation of LVI done with prognostic markers of Carcinoma Breast, namely, age of the patient, tumor size, Nottingham grade, lymph node ratio (LNR), Nottingham prognostic index (NPI), ER/PR status, and HER2/neu status. CD34 and D2-40 utilized to distinguish blood vessel, lymph vessel, and retraction artifacts and to calculate lymphatic microvessel density (LMVD) and blood microvessel density (BMVD). Statistical Analysis Used SPSS Software Package. Results LVI was associated with younger age (P = 0.001), greater tumor size (P = 0.007), higher Nottingham grade (P = 0.001), higher LNR (P = 0.001), higher NPI (P = 0.001), Negative ER Status (P = 0.001), Negative PR Status (P = 0.002), Positive HER2/neu status (P = 0.021), Higher Intratumoral BMVD (P = 0.016), Peritumoral BMVD (P = 0.001), and Intratumoral LMVD (P = 0.009). Blood vessels more commonly invaded than lymph vessels. Retraction artifacts can be mistaken for LVI without IHC. Conclusions D2-40 is a promising marker for lymphatic endothelium. LVI is a poor prognostic marker hence should be evaluated imperatively in all cases of carcinoma breast.
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Affiliation(s)
- Sonal Agarwal
- Department of Pathology, Government Medical College, Amritsar, Punjab, India
| | - Amarjit Singh
- Department of Pathology, Government Medical College, Amritsar, Punjab, India
| | - Permeet Kaur Bagga
- Department of Pathology, Government Medical College, Amritsar, Punjab, India
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Domoto H, Watanabe A, Sakata M, Shimada A, Mukai K. Invasive Solid Papillary Carcinoma of the Nipple With Pagetoid Extension and Nodal Metastasis. Int J Surg Pathol 2018; 26:573-577. [PMID: 29580118 DOI: 10.1177/1066896918766237] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
We report a case of invasive solid papillary carcinoma (SPC) of the nipple with Pagetoid extension to the skin and lymph node metastasis. SPC is an uncommon primary breast cancer accounting for less than 1% of all breast cancers. Only 2 cases occurring in the nipple have been reported. However, both cases were without Pagetoid extension or lymph node metastasis. The presently reported tumor consisted of irregularly shaped solid cell nests with delicate fibrovascular cores. The tumor cells had round nuclei with low-grade atypia and eosinophilic cytoplasm. Neuroendocrine differentiation was confirmed by immunohistochemical positivity for CD56, synaptophysin, and chromogranin A. Immunohistochemistry also confirmed the absence of myoepithelial cells around the tumor cell nests. Therefore, a diagnosis of invasive SPC was made. Additionally, tumor cell deposits in the intramammary and axillary lymph nodes were identified, and these deposits had the same histological characteristics as the invasive SPC of the nipple. The invasiveness of SPC can be difficult to determine. However, the tumor cell nests in the current case exhibited a retraction artifact, which is known to be associated with invasive carcinoma and a poor prognosis, as well as morphological patterns that have been previously identified as characteristic of invasive SPC. Although SPC is widely recognized as having a favorable outcome, the existence of exceptionally aggressive cases occurring in the nipple must be recognized. Additional cases of invasive SPC of the nipple are needed to analyze the clinicopathological correlation.
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Jain D, Tikku G, Bhadana P, Dravid C, Grover RK. The Impact of Peritumoral Retraction Clefting & Intratumoral Eosinophils on Overall Survival in Oral Squamous Carcinoma Patients. Pathol Oncol Res 2017; 25:183-189. [PMID: 29047016 DOI: 10.1007/s12253-017-0328-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 09/28/2017] [Indexed: 12/13/2022]
Abstract
This retrospective study aimed to investigate the impact of peritumoral retraction clefts (RC) and tumor-associated tissue eosinophilia (TATE) as predictors of overall survival (OS) in oral squamous cell carcinoma (OSCC) patients. Their relationships with tumor-factors were also examined. Eighty-seven OSCC cases (pTNM: I + II/III + IV; 32/55), post-curative surgery, comprised the study cohort. Three observers independently estimated the percent RC semi-quantitatively in the selected tumor sections. Additionally, stromal eosinophils were counted in ten consecutive high-power fields of intratumoral and peritumoral regions to evaluate the corresponding TATE. The percent RC ranged between 0% -90% (Mean ± SD: 16 ± 24%; Median: 5%). The stromal eosinophils were greater in peritumoral as compared to intratumoral region. The events of death and tumor recurrence were reached in 16 (18.4%) and 36 (41%) cases respectively. The 3-years OS was 69% [Median OS: 1880 days; Mean follow up: 471(Range; 36-1880) days]. Increased percent RC exhibited relationship with pathologic stage (pTNM III&IV), primary tumor (pT III&IV), tumor depth > 4 mm and categorical tumor recurrence. Additionally, peritumoral eosinophilic infiltrates increased with increasing tumor depths and muscle invasion. Kaplan-Meier curves revealed significantly reduced OS in OSCC cases exhibiting: increased percent RC (>2.5%), mild -moderate/absent intratumoral TATE (versus intense TATE) or categorical tumor recurrence. In subsequent multivariate tests, all the three variables retained significance. Additionally, intraclass correlation coefficient demonstrated acceptable internal consistency for the observers who estimated percent RC. In conclusion, RC and intratumoral TATE proved to be independent predictors of OS in our OSCC cohort. Additionally, increased percent RC pointed towards aggressive tumor behaviour.
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Affiliation(s)
- Dhruv Jain
- Department of Oncopathology, Delhi State Cancer Institute, Dilshad Garden, Delhi, 110095, India.
| | - Gargi Tikku
- Department of Oncopathology, Delhi State Cancer Institute, Dilshad Garden, Delhi, 110095, India
| | - Pallavi Bhadana
- Department of Oncopathology, Delhi State Cancer Institute, Dilshad Garden, Delhi, 110095, India
| | | | - Rajesh Kumar Grover
- Department of Clinical Oncology, Delhi State Cancer Institute, Delhi, 110095, India
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Džombeta T, Krušlin B. High Grade T1 Papillary Urothelial Bladder Cancer Shows Prominent Peritumoral Retraction Clefting. Pathol Oncol Res 2017; 24:567-574. [PMID: 28752222 DOI: 10.1007/s12253-017-0279-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 07/12/2017] [Indexed: 11/24/2022]
Abstract
Differentiation of noninvasive from invasive papillary urothelial carcinoma can be challenging due to inability of proper orientation and thermal damage of transurethrally obtained material. The aim of this study was to analyze the presence and extent of peritumoral retractions in pT1 compared to pTa papillary urothelial carcinoma. Since peritumoral retractions may result from altered expression profiles of extracellular matrix proteins, we additionally analyzed the expression of matrix metalloproteinase 2 (MMP-2) and interleukin 8 (IL-8) in these tumors. The study comprised 50 noninvasive (pTa) and 50 invasive (pT1) cases of transurethrally obtained primary papillary urothelial carcinomas. The invasive nature of nests showing peritumoral retractions was confirmed immunohistochemically using antibody against collagen IV. Staining for MMP-2 and IL-8 was evaluated semiquantitatively using immunohistochemical staining index, calculated by multiplying the percentage of positive cells and staining intensity. Peritumoral retractions were found in 32% of pT1 carcinomas but in none of the pTa carcinomas. All tumors showing peritumoral retraction were high grade tumors. There was no statistically significant correlation between the expression of MMP-2 or IL-8 and the presence of peritumoral retractions or stage of the tumor (pTa vs. pT1). A statistically significant but weak correlation was found between MMP-2 and IL-8 expression (χ2-test, p=0,015). There was no statistically significant correlation between the presence of peritumoral retractions or MMP-2 expression and tumor recurrence and progression. Our study shows that, in doubtful cases, when differentiating between pTa and pT1 stages of papillary urothelial carcinoma, the presence of peritumoral retractions could favor the diagnosis of invasive neoplasm.
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Affiliation(s)
- Tihana Džombeta
- Department of Pathology, School of Medicine, University of Zagreb, Šalata 10, 10 000, Zagreb, Croatia. .,Department of Pathology, Clinical Hospital Centre Sestre milosrdnice, Vinogradska 29, 10 000, Zagreb, Croatia.
| | - Božo Krušlin
- Department of Pathology, School of Medicine, University of Zagreb, Šalata 10, 10 000, Zagreb, Croatia.,Department of Pathology, Clinical Hospital Centre Sestre milosrdnice, Vinogradska 29, 10 000, Zagreb, Croatia
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11
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Yang YL, Liu BB, Zhang X, Fu L. Invasive Micropapillary Carcinoma of the Breast: An Update. Arch Pathol Lab Med 2017; 140:799-805. [PMID: 27472238 DOI: 10.5858/arpa.2016-0040-ra] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
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.
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Affiliation(s)
| | | | | | - Li Fu
- From the Department of Breast Pathology and Research Laboratory, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China (Drs Yang, Liu, and Fu); and the Department of Pathology, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, New Jersey (Dr Zhang). Drs Zhang and Fu jointly supervised the work
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12
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Reversed polarity of the glandular epithelial cells in micropapillary carcinoma of the large intestine and the EMA/MUC1 immunostain. Pathology 2016; 46:527-32. [PMID: 25158820 DOI: 10.1097/pat.0000000000000144] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Micropapillary carcinoma of the colon and rectum is associated with an adverse prognosis. This tumour type displays reverse polarity of the tumour cells and is stated to be characterised by an inside-out epithelial membrane antigen (EMA)/MUC1 staining. Nine cases of primary colorectal carcinoma and one omental metastasis were studied by means of immunohistochemistry, using antibodies to detect EMA, MUC1, MUC2, MUC3, MUC5AC, MUC6, CD10, CA125, carcinoembryonic antigen (CEA). The inside-out pattern staining with EMA/MUC1 ranged from diffuse circumferential through focal and partial to negative, but in some cases CEA, MUC3 and CD10 also showed this pattern staining, sometimes more clearly than did EMA or MUC1. The reverse polarity of colorectal micropapillary carcinomas is sometimes better visualised by immunostains other than EMA/MUC1.
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13
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Jung YY, Hyun CL, Jin MS, Park IA, Chung YR, Shim B, Lee KH, Ryu HS. Histomorphological Factors Predicting the Response to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer. J Breast Cancer 2016; 19:261-267. [PMID: 27721875 PMCID: PMC5053310 DOI: 10.4048/jbc.2016.19.3.261] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 07/01/2016] [Indexed: 12/18/2022] Open
Abstract
Purpose There is no standard targeted therapy for the treatment of triple-negative breast cancer (TNBC). Therefore, its management heavily depends on adjuvant chemotherapy. Using core needle biopsy, this study evaluated the histological factors of TNBC predicting the response to chemotherapy. Methods One hundred forty-three TNBC patients who received single-regimen neoadjuvant chemotherapy (NAC) with the combination of doxorubicin, cyclophosphamide, and docetaxel were enrolled. The core needle biopsy specimens acquired before NAC were used to analyze the clinicopathologic variables and overall performance of the predictive model for therapeutic response. Results Independent predictors of pathologic complete response after NAC were found to be higher number of tumor infiltrating lymphocytes (p=0.007), absence of clear cytoplasm (p=0.008), low necrosis (p=0.018), and high histologic grade (p=0.039). In the receiver operating characteristics curve analysis, the area under curve for the combination of these four variables was 0.777. Conclusion The present study demonstrated that a predictive model using the above four variables can predict therapeutic response to single-regimen NAC with the combination of doxorubicin, cyclophosphamide, and docetaxel in TNBC. Therefore, adding these morphologic variables to clinical and genomic signatures might enhance the ability to predict the therapeutic response to NAC in TNBC.
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Affiliation(s)
- Yoon Yang Jung
- Department of Pathology, Myongji Hospital, Goyang, Korea
| | - Chang Lim Hyun
- Department of Pathology, Jeju National University Hospital, Jeju, Korea
| | - Min-Sun Jin
- Department of Pathology, Bucheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Bucheon, Korea
| | - In Ae Park
- Department of Pathology, Seoul National University Hospital, Seoul, Korea
| | - Yul Ri Chung
- Department of Pathology, Seoul National University Hospital, Seoul, Korea
| | - Bobae Shim
- Department of Pathology, Seoul National University Hospital, Seoul, Korea
| | - Kyu Ho Lee
- Department of Pathology, Seoul National University Hospital, Seoul, Korea
| | - Han Suk Ryu
- Department of Pathology, Seoul National University Hospital, Seoul, Korea
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Nefedova NA, Kharlova OA, Danilova NV, Malkov PG, Gaifullin NM. [Markers of angiogenesis in tumor growth]. Arkh Patol 2016; 78:55-63. [PMID: 27340718 DOI: 10.17116/patol201678255-62] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Angiogenesis is a process of new blood vessels formation. The role of angiogenesis in growth, invasion and metastasis of malignant tumours is nowdays universally recognized. Though, investigation of mechanisms of blood vessels formation and elaboration methods for assessment of tumour angiogenesis are still up-dated. Another important concern are different aspects of usage of immunohistochemical markers of blood vessels endothelium (CD31 and CD34) for assessment of tumour aggressiveness and prognosis. The problems of malignant lymphangiogenesis are also up-to-date. The focus is on methods of immunohistochemical visualization of forming lymphatic vessels, role of podoplanin, the most reliable marker of lymphatic vessels, in their identification, and formulization of the main criteria for lymphangiogenesis estimation, its correlation with metastatic activity and prognostic potential. Studying of angiogenesis and lymph angiogenesis in malignant tumors is important and challenging direction for researching tumour progression and invention of antiangiogenic therapy.
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Affiliation(s)
- N A Nefedova
- Russian Medical Academy of Postgraduate Education Ministry of Health of Russia, Moscow, Russia; Lomonosov Moscow State University, Moscow, Russia
| | - O A Kharlova
- Lomonosov Moscow State University, Moscow, Russia
| | - N V Danilova
- Russian Medical Academy of Postgraduate Education Ministry of Health of Russia, Moscow, Russia; Lomonosov Moscow State University, Moscow, Russia
| | - P G Malkov
- Russian Medical Academy of Postgraduate Education Ministry of Health of Russia, Moscow, Russia; Lomonosov Moscow State University, Moscow, Russia
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15
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Senchukova MA, Nikitenko NV, Tomchuk ON, Zaitsev NV, Stadnikov AA. Different types of tumor vessels in breast cancer: morphology and clinical value. SPRINGERPLUS 2015; 4:512. [PMID: 26405632 PMCID: PMC4573747 DOI: 10.1186/s40064-015-1293-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2015] [Accepted: 08/30/2015] [Indexed: 02/08/2023]
Abstract
Angiogenesis is a key factor of tumor progression. Considering, that the tumor vessels are heterogeneous and differ in morphology and clinical significance, the purpose of this research was to study of the morphological features of tumor vessels and their relationship with the clinical characteristics and morphological features of breast cancer (BC). In this pilot study the tumor samples received from 59 patients with T1-T2 stages of ductal invasive carcinomas were included. The sections were stained with hematoxylin and eosin and immunohistochemically using antibodies to CD34. The morphological features and the number of different types of tumor vessels were assessed microscopically and were compared with grade, lymph node metastasis, hormone receptors, HER2/neu status and with the presence of tumor emboli in vessels (lymphovascular invasion). We identified the following types of tumor vessels in BC: the normal microvessels, the dilated capillaries of peritumoral stroma, the atypical dilated capillaries and the "cavitary" structures (CS) type-1 and type-2 relating to the "cavitary" type of angiogenesis that was described by us earlier. The number of dilated capillaries correlated with CS type-1 (p = 0.003), CS type-2 (p = 0.002), atypical dilated capillaries (p = 0.0008) and with lymphovascular invasion (p = 0.005); the presence of atypical dilated capillaries-with CS type-1 (p < 0.00001), CS type-2 (p = 0.00004), lymphovascular invasion (p = 0.0002) and with the tumor grade (p = 0.003); the number of CS type-1-with estrogen receptor (p = 0.002) and progesterone receptor (p = 0.002) status and with lymphovascular invasion (p = 0.004); the presence of CS type-2-with positive Her2/new status (p = 0.0002) and lymphovascular invasion (p = 0.01). The density of normal microvessels was not associated with other types of tumor vessels and with clinical characteristics of BC. These data indicate that varied types of tumor vessels are associated with different morphological characteristics of BC, such as hormone receptors and HER2/neu status, lymphovascular invasion. We believe that the atypical dilated capillaries are related to the "cavitary" type of angiogenesis. The strong correlations of lymphovascular invasion with CS type-1 and atypical dilated capillaries testify that the "cavitary" type of angiogenesis may play a significant role in the formation of tumor emboli in the vessels.
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Affiliation(s)
| | | | - Olesia N. Tomchuk
- />Department of Histology, Cytology and Embryology, Orenburg State Medical University, Orenburg, Russia
| | | | - Alexander A. Stadnikov
- />Department of Histology, Cytology and Embryology, Orenburg State Medical University, Orenburg, Russia
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16
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The presence of extensive retraction clefts in invasive breast carcinomas correlates with lymphatic invasion and nodal metastasis and predicts poor outcome: a prospective validation study of 2742 consecutive cases. Am J Surg Pathol 2015; 39:325-37. [PMID: 25353283 DOI: 10.1097/pas.0000000000000339] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
We previously reported that the presence of extensive retraction clefts (RC) in breast cancers correlates with increasing tumor size and grade as well as lymphatic tumor spread and predicts poor outcome. This study is a prospective validation of our prior results. Consecutive cases of invasive breast carcinoma (n=2742) were reviewed to determine the diagnoses, including histologic type, grade, presence of lymphovascular invasion (LVI), and extent of RC. No differences were found in the extent of RC between corresponding core needle biopsy and surgical samples. Extent of RC showed a significant correlation with tumor size, grade, LVI, and nodal metastasis in both core needle biopsy and surgical specimens. These associations remained significant in subset analyses of small (≤1 cm), node-negative and node-positive tumors. Extensive RC predicted poor recurrence-free (P<0.0001) and overall (P<0.0001) survival and remained significant in subset analyses of node-negative (P=0.0015 and 0.0021, respectively) and node-positive (P=0.0039 and 0.0214, respectively) cases. Carcinomas without LVI but extensive RC were associated with better outcome than carcinomas with LVI but worse than those without LVI and low RC. This prospective study confirms that the presence of extensive RC in invasive breast carcinomas correlates with aggressive tumor features and lymphatic tumor spread. Extensive RC appears to be an independent factor predictive of poor outcome in node-negative and node-positive disease. Our results support the hypothesis that RCs are the morphologic reflection of biological changes in tumor cells playing a role in lymphatic tumor spread and likely represent an early stage of LVI with similar clinical implications.
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17
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Yoo SH, Park IA, Chung YR, Kim H, Lee K, Noh DY, Im SA, Han W, Moon HG, Lee KH, Ryu HS. A histomorphologic predictive model for axillary lymph node metastasis in preoperative breast cancer core needle biopsy according to intrinsic subtypes. Hum Pathol 2014; 46:246-54. [PMID: 25496835 DOI: 10.1016/j.humpath.2014.10.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Revised: 10/06/2014] [Accepted: 10/31/2014] [Indexed: 01/08/2023]
Abstract
The aim of this study is construction of a pathologic nomogram that can predict axillary lymph node metastasis (LNM) for each intrinsic subtype of breast cancer with regard to histologic characteristics in breast core needle biopsy (CNB) for use in routine practice. A total of 534 CNBs with invasive ductal carcinoma classified into 5 intrinsic subtypes were enrolled. Eighteen clinicopathological characteristics and 8 molecular markers used in CNB were evaluated for construction of the best predictive model of LNM. In addition to conventional parameters including tumor multiplicity (P < .001), tumor size (P < .001), high histologic grade (P = .035), and lymphatic invasion (P = .017), micropapillary structure (P < .001), the presence of small cell-like crush artifact (P = .001), and overexpression of HER2 (P = .090) and p53 (P = .087) were proven to be independent predictive factors for LNM. A combination of 8 statistically independent parameters yielded the strongest predictive performance with an area under the curve of 0.760 for LNM. A combination of 6 independent variables, including tumor number, tumor size, histologic grade, lymphatic invasion, micropapillary structure, and small cell-like crush artifact produced the best predictive performance for LNM in luminal A intrinsic subtype (area under the curve, 0.791). Thus, adding these combinations of clinical and morphologic parameters in preoperative CNB is expected to enhance the accuracy of prediction of LNM in breast cancer, which might serve as another valuable tool in determining optimal surgical strategies for breast cancer patients.
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Affiliation(s)
- Su Hyun Yoo
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - In Ae Park
- Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Yul Ri Chung
- Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Hyojin Kim
- Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Keehwan Lee
- Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Dong-Young Noh
- Department of Surgery, Seoul National University Hospital, Seoul, Republic of Korea
| | - Seock-Ah Im
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Wonshik Han
- Department of Surgery, Seoul National University Hospital, Seoul, Republic of Korea
| | - Hyeong-Gon Moon
- Department of Surgery, Seoul National University Hospital, Seoul, Republic of Korea
| | - Kyung-Hun Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Han Suk Ryu
- Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea.
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Senchukova M, Kiselevsky MV. The "cavitary" type of angiogenesis by gastric cancer. Morphological characteristics and prognostic value. J Cancer 2014; 5:311-319. [PMID: 24723973 PMCID: PMC3982177 DOI: 10.7150/jca.8716] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Accepted: 03/02/2014] [Indexed: 02/05/2023] Open
Abstract
UNLABELLED The "cavitary" type of angiogenesis in patients with gastric cancer (GC) is described for the first time. MATERIAL AND METHODS The samples of tumour and adjacent gastric mucosa (GM) in 73 patients with GC who had undergone radical surgery were being studied. The sections were stained with hematoxylin and eosin (H&E) and immunohistochemically (IGH) using antibodies to CD34. RESULTS А new type of vessel formation consists of the appearance of cavitary structures (CS) in tumours and the adjacent GM, which are then lined by endothelial cells and merged into the blood vessels of the organ. We believe that the CS can be formed by means: 1) of the abruption of layers of epithelial cells (both normal and tumoral) from their underlying foundation and their desquamation into the lumen of the "obliterated" gastric glands (GG); 2) of the dilatation of the GG and thinning of their walls; 3) of the formation of "cavity" directly in the lamina propria of GM or in the tumoral stroma. It was noted that only the presence of multiple "cavitary" vessels (CV) of type-1 had been associated with the decrease of 3-year overall survival (OR=15,0, 95%CI=2,96-76,31) and relapse-free survival (OR=14,93, 95%CI=4,34-51,38). We also observed the improvement of the long-term outcomes in patients with GC having received antibacterial therapy (AT) before surgery that can be associated with its influence on the formation of CV type-1. CONCLUSION The described new type of angiogenesis is of great clinical importance.
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Affiliation(s)
| | - Mikhail V. Kiselevsky
- 2. Institute of Experimental Diagnostics and Therapy of Tumors, Russian Oncological Scientific Center named after N.N.Blokhin, Moscow, Russia
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Zhao L, Yang X, Khan A, Kandil D. Diagnostic role of immunohistochemistry in the evaluation of breast pathology specimens. Arch Pathol Lab Med 2014; 138:16-24. [PMID: 24377808 DOI: 10.5858/arpa.2012-0440-ra] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT Immunohistochemistry plays a vital role in the evaluation of breast pathology specimens. OBJECTIVE To discuss the role of myoepithelial cell markers in the evaluation of various breast lesions. Other markers, such as E-cadherin and those used to differentiate mammary carcinoma from metastatic tumors to the breast, and markers used in the differential diagnosis of Paget disease, are also discussed. DATA SOURCES Data were obtained from review of the pertinent peer-reviewed literature. CONCLUSIONS Myoepithelial cell markers vary in their sensitivity and specificity, and one should be aware of the potential pitfalls in interpretation. Using panels of 2 or more myoepithelial cell markers is always recommended, either singly or in cocktail forms. Although negative E-cadherin staining supports the diagnosis of lobular origin, positive staining does not rule it out. Immunohistochemistry can be helpful in differentiating Paget disease from its mimics. Although metastatic tumors to the breast are rare, a triple-negative immunophenotype and absence of an in situ component should be a "red flag" for such possibility, especially in patients with clinical history of an extramammary malignancy.
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Affiliation(s)
- Larry Zhao
- From the Department of Pathology, University of Massachusetts, UMass Memorial Medical Center, Worcester, Massachusetts
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Hughes C, Iqbal-Wahid J, Brown M, Shanks JH, Eustace A, Denley H, Hoskin PJ, West C, Clarke NW, Gardner P. FTIR microspectroscopy of selected rare diverse sub-variants of carcinoma of the urinary bladder. JOURNAL OF BIOPHOTONICS 2013; 6:73-87. [PMID: 23125109 DOI: 10.1002/jbio.201200126] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2012] [Revised: 10/01/2012] [Accepted: 10/01/2012] [Indexed: 06/01/2023]
Abstract
Urothelial carcinomas of the bladder are a heterogeneous group of tumours, although some histological sub-variants are rare and sparsely reported in the literature. Diagnosis of sub-variants from conventional urothelial carcinoma can be challenging, as they may mimic the morphology of other malignancies or benign tumours and therefore their distinction is important. For the first time, the spectral pathology of some of these sub-variants has been documented by infrared microspectroscopy and an attempt made to profile their biochemistry. It is important not only to identify and separate the cancer-associated epithelial tissue spectra from common tissue features such as stroma or blood, but also to detect the signatures of tumour sub-variants. As shown, their spectroscopic signals can change dramatically as a consequence of differentiation. Example cases are discussed and compared with histological evaluations.
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Affiliation(s)
- Caryn Hughes
- Manchester Institute of Biotechnology, University of Manchester, Manchester, UK
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21
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Zaorsky NG, Patil N, Freedman GM, Tuluc M. Differentiating lymphovascular invasion from retraction artifact on histological specimen of breast carcinoma and their implications on prognosis. J Breast Cancer 2012; 15:478-80. [PMID: 23346180 PMCID: PMC3542859 DOI: 10.4048/jbc.2012.15.4.478] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Accepted: 12/10/2012] [Indexed: 11/30/2022] Open
Abstract
On a pathological specimen of breast cancer cells, retraction artifact during histological processing mimics true lymphovascular invasion (LVI). The accurate determination of the presence or absence of LVI is a factor in determining risk of having a positive sentinel node, or having additional positive axillary nodes after a positive sentinel node biopsy in women with early-stage breast cancer. The determination of nodal risk influences the decision of the treating physicians as to whether a sentinel node biopsy or completion axillary dissection is necessary. On slide preparation, ideal factors favoring true LVI include: a definite endothelial lining, with endothelial nuclei that seem to protrude into the lymphatic space; invasion in one lymphatic vessel (LV) lumen with nearby cancer glands that have minimal or no retraction; a tumor embolus in a LV clear lumen with outside nearby tumor bulk; a tumor embolus that is different in shape than its surrounding clear LV space; and a positive stain for fibrin, CD31, or CD34 on tumor embolus periphery.
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Affiliation(s)
- Nicholas George Zaorsky
- Department of Radiation Oncology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, USA
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Acs G, Paragh G, Rakosy Z, Laronga C, Zhang PJ. The extent of retraction clefts correlates with lymphatic vessel density and VEGF-C expression and predicts nodal metastasis and poor prognosis in early-stage breast carcinoma. Mod Pathol 2012; 25:163-77. [PMID: 22020194 DOI: 10.1038/modpathol.2011.138] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Although the earliest feature of disseminated disease in breast cancer is regional lymph node involvement, little is known about the mechanisms whereby cancer cells interact with lymphatic endothelial cells and enter the lymphatic system. We have previously reported that the extensive presence of retraction clefts in breast carcinomas highly significantly correlates with lymphatic tumor spread and predicts poor outcome, suggesting that retraction clefts are not just fixation artifacts, but real potential spaces that are exaggerated by tissue processing and may reflect an early stage of lymphatic invasion. In this study, we examined the correlation between the extent of retraction clefts and lymphangiogenesis, as assessed by lymphatic vessel density and vascular endothelial growth factor-C (VEGF-C) expression in a series of 256 early-stage breast carcinomas. The presence and extent of retraction clefts around tumor cell nests was determined by review of all hematoxylin- and eosin-stained tumor sections. Lymphatic vessels were detected by podoplanin immunohistochemistry and lymphatic vessel density was measured using the hot-spot method. The expression of VEGF-C in the tumor cells was determined by immunohistochemistry and analyzed semiquantitatively on a four-tiered scale. High levels of retraction clefts, peritumor lymphatic vessel density and VEGF-C expression at the invasive edge in breast carcinomas significantly correlated with tumor size, histological grade, lymphatic invasion and nodal metastasis. Breast carcinomas showing extensive retraction clefts (>20% of tumor volume) were found to have significantly higher lymphatic vessel density and VEGF-C expression levels compared to tumors without this feature. High retraction clefts, peritumor lymphatic vessel density and VEGF-C expression predicted poor outcome in breast carcinomas. Our results support the hypothesis that retraction clefts are real potential spaces that may represent 'pre-lymphatic spaces' facilitating initial lymphatic invasion and that growth factors secreted by the tumor cells may stimulate tumor-associated lymphangiogenesis by promoting the endothelialization of these 'pre-lymphatic channels'.
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Affiliation(s)
- Geza Acs
- Department of Anatomic Pathology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
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23
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Lymphatic tumor emboli detected by D2-40 immunostaining can more accurately predict lymph-node metastasis. World J Surg 2011; 35:2031-7. [PMID: 21667194 DOI: 10.1007/s00268-011-1143-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Resected specimens of superficial squamous cell carcinoma of the esophagus (SSCCE) underwent D2-40 immunostaining to accurately assess lymphatic tumor emboli (LY) and to analyze correlations between LY and lymph node metastasis (N). This present study was designed to determine the accuracy of LY grade for predicting the risk of N. MATERIALS AND METHODS We studied 75 patients with SSCCE who underwent surgical resection of their tumors. Resected specimens were sliced into continuous sections at 5 mm intervals. Intramucosal cancers are classified into three groups (m1, m2, m3), and submucosal cancers are also divided into three groups (sm1, sm2, sm3). The numbers of LY present in lymphatic ducts on D2-40 immunostaining, venous tumor emboli (V) on CD34 immunostaining, and lymphatic tumor emboli (ly) and V on hematoxylin-eosin staining (HE) and elastica van Gieson staining (EVG) were counted for each case. The presence of lymphatic tumor emboli was graded according to the total number of LY per case as follows: 0, LY0; 1 to 2, LY1; 3 to 9, LY2; and 10 or more, LY3. RESULTS All m1 and m2 cases were LY- and N- Lymphatic tumor emboli were present in 54% of m3 cases, 70% of sm1 cases, 54% of sm2 cases, and 75% of sm3 cases. Determination of N was positive in 18% of m3 cases, 47% of sm1 cases, 36% of sm2 cases, and 62% of sm3 cases. The frequency of LY significantly correlated with the number of N (p < 0.0001). Multiple regression analysis showed that only LY and V significantly correlated with N. When the detection rate of N was compared between LY and ly, LY was superior to ly in terms of specificity, accuracy, positive predictive value, and false positive rate. As for LY grade, N was positive in 39.1% of LY1 cases, 81.8% of LY2 cases, and 100% of LY3 cases. Even in LY-, N was positive in one sm1 case and in two sm2 cases. In the sm1 case, the depth of invasion was 350 μm from the lower margin of the muscularis mucosae. CONCLUSIONS Evaluation of lymphatic invasion on the basis of LY is more accurate for the prediction of N than conventional techniques, and LY grade strongly correlates with N. In patients with SSCCE, mucosal cancers (m1, m2, and m3) and submucosal cancers with a depth of invasion of ≤ 200 μm from the lower margin of the muscularis mucosae on endoscopic mucosal resection have a low risk of N if the number of LY is 0. Endoscopic mucosal resection alone can provide good treatment outcomes in such patients.
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Periacinar retraction clefting and d2-40 expression in prostatic adenocarcinoma. Pathol Oncol Res 2011; 18:365-70. [PMID: 21910091 DOI: 10.1007/s12253-011-9453-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2011] [Accepted: 08/11/2011] [Indexed: 12/11/2022]
Abstract
Retraction clefting is known to appear in various types of tumors, but it has only recently been recognized as a specific histological phenomenon. Previously, it was considered merely a laboratory procedure artifact, but lately, there have been some assumptions that peritumoral retractions actually represent lymphatic spaces. In our study, we analyzed neoplastic glands in 52 specimens of prostatic adenocarcinoma. Immunohistochemical analysis was performed using D2-40 antibody, to highlight lymphatic endothelium and thereby differentiate actual lymph vessels or lymphovascular invasion from periacinar retractions. Our results showed that the number of lymph vessels was significantly lower in tumorous tissue compared to adjacent normal prostatic tissue. On the other hand, the number of lymph vessels in tumorous tissue was significantly higher than the number of lymph vessels mimicking periacinar retractions. Overall, the number of lymph vessels mimicking periacinar clefts was particularly low. These results are in accordance with our previous studies, which had shown that periacinar clefting appears due to lack of basal cells and stromal changes around tumorous acini. Also, these results support our hypothesis that retractions do not represent lymph vessels but should be considered a distinct entity, which is proven to be helpful both as diagnostic and predictive factor.
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25
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Mahooti S, Porter K, Alpaugh ML, Ye Y, Xiao Y, Jones S, Tellez JD, Barsky SH. Breast carcinomatous tumoral emboli can result from encircling lymphovasculogenesis rather than lymphovascular invasion. Oncotarget 2011; 1:131-47. [PMID: 21297224 DOI: 10.18632/oncotarget.100609] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
The canonical view of the origin of tumor lymphovascular emboli is that they usually originate from lymphovascular invasion as part of a multistep metastatic process. Recent experimental evidence has suggested that metastasis can occur earlier than previously thought and we found evidence that tumor emboli formation can result from the short-circuiting step of encircling lymphovasculogenesis. Experimentally, we used a xenograft of human inflammatory breast cancer (MARY-X), a model that exhibited florid tumor emboli, to generate tumoral spheroids in vitro. In observational studies, we chose human breast carcinoma cases where there appeared to be a possible transition of in situ carcinoma to lymphovascular emboli without intervening stromal invasion. These cases were studied by morphometry as well as IHC with tumor proliferation (Ki-67) and adhesion (E-cadherin) markers, myoepithelial (p63), as well as endothelial (podoplanin [D2-40], CD31, VEGFR-3, Prox-1) markers. Unlabelled spheroids coinjected with either GFP or RFP-human myoepithelial cells or murine embryonal fibroblasts (MEFs) gave rise to tumors which exhibited GFP/RFP immunoreactivity within the cells lining the emboli-containing lymphovascular channels. In vitro studies demonstrated that the tumoral spheroids induced endothelial differentiation of cocultured myoepithelial cells and MEFs, measured by real time PCR and immunofluorescence. In humans, the in situ clusters exhibited similar proliferation, E-cadherin immunoreactivity and size as the tumor emboli (p =.5), suggesting the possibility that the latter originated from the former. The in situclusters exhibited a loss (50%-100%) of p63 myoepithelial immunoreactivity but not E-cadherin epithelial immunoreactivity. The tumor emboli were mainly present within lymphatic channels whose dual p63/CD31, p63/D2-40 and p63/VEGFR-3 and overall weak patterns of D2-40/CD31/VEGFR-3 immunoreactivities suggested that they represented immature and newly created vasculature derived from originally myoepithelial-lined ducts. Collectively both experimental as well as observational studies suggested the possibility that these breast cancer emboli resulted from encircling lymphovasculogenesis rather than conventional lymphovascular invasion.
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Affiliation(s)
- Sepi Mahooti
- Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA
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26
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Tomas D, Spajić B, Milošević M, Demirović A, Marušić Z, Krušlin B. Extensive retraction artefact predicts biochemical recurrence-free survival in prostatic carcinoma. Histopathology 2011; 58:447-54. [PMID: 21323967 DOI: 10.1111/j.1365-2559.2011.03769.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
AIMS To determine whether the presence and extent of peritumoral retraction artefact could be used to predict biochemical recurrence-free survival in prostatic carcinoma. METHODS AND RESULTS The study included 162 consecutive patients treated by radical retropubic prostatectomy and bilateral lymphadenectomy for clinically localized prostatic carcinoma. A variable degree of retraction artefact was present in all 162 analysed tumours. The extent of retraction artefact in prostatic carcinomas ranged from 5% to 55% with a median value of 15% (interquartile range 10-25%). We found no correlation between the extent of retraction artefact in the tumours and patient's age (P=0.608), preoperative (P=0.362) and postoperative (P=0.279) Gleason score or lymph node metastases (P=0.084). In contrast, the extent of retraction artefact correlated with high preoperative prostate-specific antigen (P<0.001), short follow-up time (P<0.001), seminal vesicle invasion and/or extracapsular extension of the tumour (T3 stage tumours) (P<0.001) and positive surgical margins (P<0.001). Furthermore, extensive retraction artefact was associated with poor biochemical recurrence-free survival in both univariate (P<0.001) and multivariate analyses (P=0.013). CONCLUSION The presence of extensive retraction artefact in prostatic carcinoma correlates with tumour characteristics signifying aggressive behaviour and indicates poor biochemical recurrence-free survival.
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Affiliation(s)
- Davor Tomas
- Department of Pathology, Sestre milosrdnice University Hospital, Zagreb, Croatia.
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27
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Kuba S, Ohtani H, Yamaguchi J, Hayashi H, Uga T, Kanematsu T, Shimokawa I. Incomplete inside-out growth pattern in invasive breast carcinoma: association with lymph vessel invasion and recurrence-free survival. Virchows Arch 2011; 458:159-69. [PMID: 21221635 DOI: 10.1007/s00428-010-1033-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2010] [Revised: 12/16/2010] [Accepted: 12/20/2010] [Indexed: 10/18/2022]
Abstract
Invasive micropapillary carcinoma (IMPC) is a rare subtype of epithelial tumor of the breast listed in the 2003 World Health Organization histologic classification of tumors of the breast. It is characterized by inside-out micropapillary morphology, frequent lymph vessel invasion (LVI), and lymph node metastasis; however, its etiology remains unknown. This study investigated the incomplete inside-out growth pattern (IGP) in invasive ductal carcinoma, not otherwise specified (NOS), and examined the association between incomplete IGP and clinicopathologic features, including the presence of intratumoral lymph vessels (ILV), LVI, nodal metastasis, and prognosis. Tumor tissues from 166 invasive duct carcinomas NOS and 10 IMPCs were immunostained using an anti-epithelial membrane antigen antibody to detect IGP and with D2-40 antibody to determine the presence of ILV and LVI. Incomplete IGP was detected focally in 88 (53%) of 166 invasive duct carcinomas NOS. Transition areas between IMPC and invasive duct carcinoma NOS also showed prominent incomplete IGP in 9 (90%) of 10 IMPCs. Incomplete IGP in invasive duct carcinomas NOS was associated with larger tumor size, higher frequencies of ILV, LVI, nodal metastasis, and poorer recurrence-free survival by univariate analysis. Incomplete IGP, ILV, and tumor size independently affected LVI by multivariate analysis. These findings indicate that incomplete IGP of tumor cell clusters is not uncommon and is a useful tool for predicting LVI in invasive duct carcinoma NOS of the breast.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/analysis
- Breast Neoplasms/metabolism
- Breast Neoplasms/mortality
- Breast Neoplasms/pathology
- Carcinoma, Ductal, Breast/metabolism
- Carcinoma, Ductal, Breast/mortality
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Papillary/metabolism
- Carcinoma, Papillary/mortality
- Carcinoma, Papillary/pathology
- Disease-Free Survival
- Female
- Humans
- Immunohistochemistry
- Kaplan-Meier Estimate
- Lymphatic Metastasis
- Middle Aged
- Mucin-1/biosynthesis
- Prognosis
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Affiliation(s)
- Sayaka Kuba
- Department of Surgery, Graduate School of Biomedical Science, Nagasaki University, Nagasaki, Japan
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28
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Invasive ductal carcinomas of the breast showing partial reversed cell polarity are associated with lymphatic tumor spread and may represent part of a spectrum of invasive micropapillary carcinoma. Am J Surg Pathol 2010; 34:1637-46. [PMID: 20975342 DOI: 10.1097/pas.0b013e3181f5539c] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Invasive micropapillary carcinomas (IMPC) of the breast are aggressive tumors frequently associated with lymphatic invasion and nodal metastasis even when micropapillary (MP) differentiation is very focal within the tumors. We have noticed that some breast carcinomas showing lymphatic spread but lacking histologic features of IMPC have occasional tumor cell clusters reminiscent of those of IMPC without the characteristic prominent retraction artifact. To study the clinicopathologic significance of such features, we prospectively selected 1323 invasive ductal carcinomas and determined the presence and extent of MP differentiation and retraction artifact in the tumors. One representative tumor block per case was used for immunostaining for epithelial membrane antigen (EMA). Partial reverse cell polarity (PRCP) was defined as prominent linear EMA reactivity on at least part of the periphery of tumor cell clusters usually associated with decreased cytoplasmic staining. The clinicopathologic features of carcinomas with PRCP were compared with IMPC and invasive ductal (no special type) carcinomas without this feature. Of the 1323 cases, 96 (7.3%) and 92 (7.0%) showed MP features and the presence of PRCP, respectively. We found that the presence of both PRCP and MP features were strongly associated with decreased cytoplasmic EMA immunoreactivity and the presence of lymphatic invasion and nodal metastasis, even if such features were present only very focally. Our results suggest that breast carcinomas with PRCP may have the same implication as MP differentiation and these tumors may represent part of a spectrum of IMPC. Complete or partial reversal of cell polarity may play a significant role in lymphatic tumor spread.
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29
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Interobserver Reproducibility in the Diagnosis of Invasive Micropapillary Carcinoma of the Urinary Tract Among Urologic Pathologists. Am J Surg Pathol 2010; 34:1367-76. [DOI: 10.1097/pas.0b013e3181ec86b3] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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30
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Pseudoangiomatous stromal hyperplasia: An observation on its microscopic involvement in breast carcinoma and the presence of lymph node metastases. Oncol Lett 2010; 1:805-807. [PMID: 22966384 DOI: 10.3892/ol_00000141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2010] [Accepted: 06/18/2010] [Indexed: 11/05/2022] Open
Abstract
The spaces of pseudoangiomatous stromal hyperplasia (PASH) are postulated to be important in the intramammary spread of breast carcinoma. The present study aimed to note the prevalence of inconspicuous, microscopic foci of PASH (identified as CD34+ve, CD31-ve and D2-40-ve spaces containing tumour emboli) involved in breast carcinoma and to establish the significance of its relationship to lymph node metastases. A total of 80 cases of breast carcinoma were examined for microscopic foci of PASH permeated by carcinoma and, of the four cases found to demonstrate such involvement, three had lymph node metastases.
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31
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Mahooti S, Porter K, Alpaugh ML, Ye Y, Xiao Y, Jones S, Tellez JD, Barsky SH. Breast carcinomatous tumoral emboli can result from encircling lymphovasculogenesis rather than lymphovascular invasion. Oncotarget 2010; 1:131-147. [PMID: 21297224 PMCID: PMC3058877 DOI: 10.18632/oncotarget.117] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2010] [Accepted: 05/23/2010] [Indexed: 11/25/2022] Open
Abstract
The canonical view of the origin of tumor lymphovascular emboli is that they usually originate from lymphovascular invasion as part of a multistep metastatic process. Recent experimental evidence has suggested that metastasis can occur earlier than previously thought and we found evidence that tumor emboli formation can result from the short-circuiting step of encircling lymphovasculogenesis. Experimentally, we used a xenograft of human inflammatory breast cancer (MARY-X), a model that exhibited florid tumor emboli, to generate tumoral spheroids in vitro. In observational studies, we chose human breast carcinoma cases where there appeared to be a possible transition of in situ carcinoma to lymphovascular emboli without intervening stromal invasion. These cases were studied by morphometry as well as IHC with tumor proliferation (Ki-67) and adhesion (E-cadherin) markers, myoepithelial (p63), as well as endothelial (podoplanin [D2-40], CD31, VEGFR-3, Prox-1) markers. Unlabelled spheroids coinjected with either GFP or RFP-human myoepithelial cells or murine embryonal fibroblasts (MEFs) gave rise to tumors which exhibited GFP/RFP immunoreactivity within the cells lining the emboli-containing lymphovascular channels. In vitro studies demonstrated that the tumoral spheroids induced endothelial differentiation of cocultured myoepithelial cells and MEFs, measured by real time PCR and immunofluorescence. In humans, the in situ clusters exhibited similar proliferation, E-cadherin immunoreactivity and size as the tumor emboli (p =.5), suggesting the possibility that the latter originated from the former. The in situclusters exhibited a loss (50%-100%) of p63 myoepithelial immunoreactivity but not E-cadherin epithelial immunoreactivity. The tumor emboli were mainly present within lymphatic channels whose dual p63/CD31, p63/D2-40 and p63/VEGFR-3 and overall weak patterns of D2-40/CD31/VEGFR-3 immunoreactivities suggested that they represented immature and newly created vasculature derived from originally myoepithelial-lined ducts. Collectively both experimental as well as observational studies suggested the possibility that these breast cancer emboli resulted from encircling lymphovasculogenesis rather than conventional lymphovascular invasion.
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Affiliation(s)
- Sepi Mahooti
- Department of Pathology and Center for Biostatistics, The Ohio State University College of Medicine, Columbus, Ohio 43210
| | - Kyle Porter
- Center for Biostatistics, The Ohio State University College of Medicine, Columbus, Ohio 43210
| | | | - Yin Ye
- University of Nevada School of Medicine, Reno, NV 89557
| | - Yi Xiao
- Department of Pathology and Center for Biostatistics, The Ohio State University College of Medicine, Columbus, Ohio 43210
| | - Susie Jones
- Department of Pathology and Center for Biostatistics, The Ohio State University College of Medicine, Columbus, Ohio 43210
| | | | - Sanford H. Barsky
- University of Nevada School of Medicine, Reno, NV 89557
- Nevada Cancer Institute, Las Vegas, NV 89135
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McKenney JK, Amin MB, Epstein JI, Grignon DJ, Oliva E, Reuter VE, Srigley JR, Humphrey PA. Protocol for the examination of specimens from patients with carcinoma of the urethra. Arch Pathol Lab Med 2010; 134:345-50. [PMID: 20196662 DOI: 10.5858/134.3.345] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Jesse K McKenney
- Department of Pathology and Urology, Stanford University Medical Center, California, USA
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33
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Khanifar E, Stamos MJ, Billings TL, Wu MLC. Contemporary Evaluation of Colorectal Carcinoma in Specimens from Endoscopic Biopsies. Lab Med 2009. [DOI: 10.1309/lm8trjp8jy7sstsu] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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34
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Yang Z, Adams AL, Hameed O. Attenuated Podoplanin Staining in Breast Myoepithelial Cells. Appl Immunohistochem Mol Morphol 2009; 17:425-30. [DOI: 10.1097/pai.0b013e31819d2281] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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35
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Sangoi AR, Higgins JP, Rouse RV, Schneider AG, McKenney JK. Immunohistochemical comparison of MUC1, CA125, and Her2Neu in invasive micropapillary carcinoma of the urinary tract and typical invasive urothelial carcinoma with retraction artifact. Mod Pathol 2009; 22:660-7. [PMID: 19270645 DOI: 10.1038/modpathol.2009.16] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
On the basis of recent clinical studies, some urologic oncologists do not offer bladder-sparing therapy for patients diagnosed with micropapillary carcinoma of the urinary bladder, even in the setting superficially invasive disease. Unfortunately, the distinction of invasive micropapillary carcinoma from typical invasive urothelial carcinoma with prominent retraction artifact may be difficult in some cases. In this study, we compared the immunophenotype of invasive micropapillary carcinoma to invasive urothelial carcinoma with retraction artifact using antibodies previously reported as specific for micropapillary carcinoma. Immunohistochemical staining was performed on 24 invasive micropapillary carcinomas of the urinary tract and 24 case controls of invasive urothelial carcinoma with retraction artifact using monoclonal antibodies MUC1, CA125, and Her2Neu. The staining extent and intensity for MUC1 and CA125 were scored on one representative section per case. Immunostaining for Her2Neu was scored based on the 2007 CAP/ASCO guidelines for breast carcinoma. Basal ('reverse-apical') MUC1 staining was identified in 23 of the 24 (96%) invasive micropapillary carcinomas and in 15 of the 24 (63%) invasive urothelial carcinomas with retraction artifact (P=0.0102). Membranous reactivity with CA125 was seen in 8 of the 24 (33%) invasive micropapillary carcinomas and in 3 of the 24 (13%) invasive urothelial carcinomas with retraction artifact (P=0.1681). Positive (3+) membranous Her2Neu staining was present in 6 of 24 (25%) invasive micropapillary carcinomas and in 2 of the 24 (8%) invasive urothelial carcinomas with retraction artifact (P=0.2448). The specificity for invasive micropapillary carcinoma vs invasive urothelial carcinoma with retraction artifact using antibodies MUC1, CA125, and Her2Neu was 37, 87, and 92%, respectively. Invasive micropapillary carcinoma more commonly showed immunoreactivity for MUC1, CA125, and Her2Neu compared to invasive urothelial carcinoma with retraction artifact, but only MUC1 reached statistical significance. The lack of specificity of these evaluated markers for invasive micropapillary carcinoma limits their utility in the distinction from invasive urothelial carcinoma with retraction artifact, especially given the potentially significant therapeutic implications.
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Affiliation(s)
- Ankur R Sangoi
- Department of Pathology, Stanford University, Stanford, CA 94305, USA.
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36
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The presence of micropapillary features and retraction artifact in core needle biopsy material predicts lymph node metastasis in breast carcinoma. Am J Surg Pathol 2009; 33:202-10. [PMID: 18987549 DOI: 10.1097/pas.0b013e318185e171] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Retraction artifact around tumor cell nests is a characteristic feature of invasive micropapillary carcinoma (IMPC), a special type of breast cancer commonly associated with nodal metastasis. We have recently reported that the extent of retraction artifact in usual invasive ductal carcinomas (IDC) is also a strong predictor of nodal metastasis. We examined whether the presence and extent of micropapillary features and retraction artifact in core needle biopsy of breast cancers can predict nodal metastasis in a prospective series of 47 IMPC and 424 IDC. Micropapillary features were present on core needle biopsy in 28 of 47 IMPC cases. Nodal metastases were found in 21 of 28 and 14 of 19 IMPC cases with and without micropapillary features present on core needle biopsy, respectively. Lymph node metastasis was significantly associated with the presence of micropapillary features, but not with its extent within these tumors. The presence of extensive retraction artifact in core needle biopsy samples of IDC also showed a significant association with nodal metastasis. Our results indicate that the presence of micropapillary features or extensive retraction artifact on core needle biopsy of breast carcinoma can predict nodal metastasis. Our results support the notion that the characteristic clear spaces separating the tumor cells from the stroma in IMPC and IDC of the breast are not a random artifactual phenomenon simply resulting from tissue fixation and processing, but rather they are likely related to altered tumor-stromal interactions, which might have an important role in lymphatic tumor spread.
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37
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Bujas T, Pavić I, Leniček T, Mijić A, Krušlin B, Tomas D. Peritumoral Retraction Clefting Correlates with Advanced Stage Squamous Cell Carcinoma of the Esophagus. Pathol Oncol Res 2008; 14:443-7. [DOI: 10.1007/s12253-008-9038-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2008] [Accepted: 03/20/2008] [Indexed: 11/25/2022]
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38
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Lymph vascular invasion in invasive mammary carcinomas identified by the endothelial lymphatic marker D2-40 is associated with other indicators of poor prognosis. BMC Cancer 2008; 8:64. [PMID: 18307818 PMCID: PMC2294134 DOI: 10.1186/1471-2407-8-64] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2007] [Accepted: 02/29/2008] [Indexed: 11/10/2022] Open
Abstract
Background Immunohistochemical studies of lymphatic vessels have been limited by a lack of specific markers. Recently, the novel D2-40 antibody, which selectively marks endothelium of lymphatic vessels, was released. The aim of our study is to compare lymphatic and blood vessel invasion detected by hematoxylin and eosin (H&E) versus that detected by immunohistochemistry, relating them with morphologic and molecular prognostic factors. Methods We selected 123 cases of invasive mammary carcinomas stratified into three subgroups according to axillary lymph node status: macrometastases, micrometastases, and lymph node negative. Lymphatic (LVI) and blood (BVI) vessel invasion were evaluated by H&E and immunohistochemistry using the D2-40 and CD31 antibodies, and related to histologic tumor type and grade, estrogen and progesterone receptors, E-cadherin, Ki67, p53, and Her2/neu expression. Results LVI was detected in H&E-stained sections in 17/123 cases (13.8%), and in D2-40 sections in 35/123 cases (28.5%) (Kappa = 0.433). BVI was detected in H&E-stained sections in 5/123 cases (4.1%), and in CD31 stained sections in 19/123 cases (15.4%) (Kappa = 0.198). LVI is positively related to higher histologic grade (p = 0.013), higher Ki67 expression (p = 0.00013), and to the presence of macrometastases (p = 0.002), and inversely related to estrogen (p = 0.0016) and progesterone (p = 0.00017) receptors expression. Conclusion D2-40 is a reliable marker of lymphatic vessels and is a useful tool for lymphatic emboli identification in immunostained sections of breast carcinomas with higher identification rates than H&E. Lymphatic vessel invasion was related to other features (high combined histologic grade, high Ki67 score, negative hormone receptors expression) associated with worse prognosis, probable reflecting a potential for lymphatic metastatic spread and aggressive behavior.
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39
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Rabban JT, Chen YY. D2-40 expression by breast myoepithelium: potential pitfalls in distinguishing intralymphatic carcinoma from in situ carcinoma. Hum Pathol 2008; 39:175-83. [DOI: 10.1016/j.humpath.2007.06.018] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2007] [Revised: 06/25/2007] [Accepted: 06/28/2007] [Indexed: 11/15/2022]
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40
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Detection of lymphovascular invasion in early breast cancer by D2-40 (podoplanin): a clinically useful predictor for axillary lymph node metastases. Breast Cancer Res Treat 2007; 112:503-11. [DOI: 10.1007/s10549-007-9875-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2007] [Accepted: 12/17/2007] [Indexed: 10/22/2022]
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41
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Lenicek T, Szerda F, Demirović A, Mijić A, Kruslin B, Tomas D. Pleomorphic ductal carcinoma of the breast with predominant micropapillary features. Pathol Int 2007; 57:694-7. [PMID: 17803659 DOI: 10.1111/j.1440-1827.2007.02159.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
An 83-year-old woman with long-standing chronic ischemic cardiac and obstructive pulmonary disease, presented with a painless tumor in her right breast. Microscopically the tumor consisted of micropapillary formations and loosely cohesive nests and strands of large, highly pleomorphic cells. Micropapillary formations were surrounded by peritumoral retraction clefting, and the papillae lacked a true fibrovascular core. Multinucleated giant and bizarre tumor cells were also present and numerous. Within the tumor a high-grade intraductal component with the same cell morphology and necrosis and mucin production was found. Micropapillary pattern occupied approximately 60% of the tumor mass, loosely cohesive nests and strands approximately 20% and an intraductal component was noted in approximately 20% of the tumor mass. On immunohistochemistry the tumor cells were positive for pan-cytokeratin, epithelial membrane antigen (EMA), S100 protein and E-cadherin while estrogen and progesterone receptors, HER2-neu and Bcl2 were negative. EMA staining was diffuse and observed in the outer and inner margins of neoplastic nests. The diagnosis of pleomorphic breast carcinoma with predominant micropapillary features was established. In summary, micropapillary carcinoma can be distinguished from other types of breast carcinoma with micropapillary growth pattern on the basis of reverse cell polarity, which is easily confirmed on immunohistochemistry.
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MESH Headings
- Aged, 80 and over
- Biomarkers, Tumor/analysis
- Breast Neoplasms/chemistry
- Breast Neoplasms/pathology
- Breast Neoplasms/surgery
- Carcinoma, Ductal, Breast/chemistry
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Ductal, Breast/surgery
- Carcinoma, Papillary/chemistry
- Carcinoma, Papillary/pathology
- Carcinoma, Papillary/surgery
- Female
- Humans
- Immunohistochemistry
- Treatment Outcome
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Affiliation(s)
- Tanja Lenicek
- Ljudevit Jurak Department of Pathology, Sestre Milosrdnice University Hospital, Zagreb, Croatia
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