Journal of Pathology and Translational Medicine

Original Articles

Cancer Subtypes of Breast Carcinoma with Micropapillary and Mucinous Component Based on Immunohistochemical Profile.: Sun Young Min, Eun Jung Jung, Hyesil Seol, In Ae Park; Korean J Pathol. 2011;45(2):125-131.; DOI: https://doi.org/10.4132/KoreanJPathol.2011.45.2.125

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BACKGROUND
Micropapillary carcinoma (MPC) is known to have a worse prognosis than the other subtypes of breast cancer. Occasionally, MPC is observed in association with invasive ductal carcinoma not otherwise specified (IDC NOS), as well as mucinous carcinoma.
METHODS
We examined the immunohistochemical expression of an estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) in 127 cases of surgically resected MPC or IDC NOS with MPC. Further, we classified these cases based on their immunohistochemical profile.
RESULTS
Among the IDC NOS with MPC cases, 47 were luminal A (62.7%), 10 were luminal B (13.3%), and 9 were HER2 (12.0%). The MPC cases included 4 luminal A (50.0%), 2 luminal B (25.0%) and 1 HER2 (12.5%) subtypes. Of the mucinous carcinomas with MPC, 4 were grouped as luminal A (57.1%), 1 as luminal B (14.3%), and 2 as HER2 (28.6%) subtypes. However, among the mucinous carcinomas, 33 were categorized as luminal A (89.2%), 3 as luminal B (8.1%), and 1 as HER2 (2.7%) subtype, indicating a low incidence of HER2 subtype as compared to the other subtypes.
CONCLUSIONS
The luminal B and HER2 subtypes were prevalent in carcinomas with MPC. This result explains the poor prognosis of breast carcinomas with an MPC pattern.

Citations

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Investigation of Clinical Histopathologic Features and Metabolic Parameters of ¹⁸F-FDG PET/CT in Invasive Breast Carcinoma with a Micropapillary Component
Elife Akgün, Göksel Alçın, Esra Canan Kelten Talu, Tevfik Fikret Çermik, Tuçe Söylemez Akkurt, Ebru Şen, Esra Arslan
Molecular Imaging and Radionuclide Therapy.2023; 32(3): 221. CrossRef
Micropapillary Breast Carcinoma: From Molecular Pathogenesis to Prognosis
Georgios-Ioannis Verras, Levan Tchabashvili, Francesk Mulita, Ioanna Maria Grypari, Sofia Sourouni, Evangelia Panagodimou, Maria-Ioanna Argentou
Breast Cancer: Targets and Therapy.2022; Volume 14: 41. CrossRef
Micropapillary variant of mucinous breast carcinoma: A distinct subtype
Katrina Collins, Andrew Ricci
The Breast Journal.2018; 24(3): 339. CrossRef
Prognostic Significance of a Micropapillary Pattern in Pure Mucinous Carcinoma of the Breast: Comparative Analysis with Micropapillary Carcinoma
Hyun-Jung Kim, Kyeongmee Park, Jung Yeon Kim, Guhyun Kang, Geumhee Gwak, Inseok Park
Journal of Pathology and Translational Medicine.2017; 51(4): 403. CrossRef

The p53 Mutation and DNA Ploidy in Human Metastatic Breast Cancer.: Seong Jin Cho, Ae Ree Kim, Nam Hee Won; Korean J Pathol. 1997;31(2):135-144.

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Abstract PDF: The p53 gene, one of the tumor suppressor genes, is believed to play an important role through mutation and overexpression in the progression of various human malignant tumors. To compare the p53 mutation status between the primary and metastatic lesions of breast cancers and to investigate the mutational pattern of p53, immunohistochemistry (IHC) and polymerase chain reaction and single strand conformational polymorphism (PCR-SSCP) were performed in 25 cases of breast cancers with paraffin embedded tissue. Mutant protein products or point mutation were detected through IHC or PCR-SSCP method. And flow cytometrical (FCM) analysis were performed in the same paraffin blocks to correlate the DNA ploidy and p53 mutation. The following results are summarized. 1. The detection of the p53 gene mutation and overexpression of the p53 protein were measured in 40% and 48%, respectively, in 25 primary tumors, either or both methods was detected in 64%. 2. A concordance rate of the p53 protein expression between the primary and metastatic lesions of 25 breast cancers was 100%, but the concordance rate of the p53 gene mutation was 72%. 3. The correlation between the p53 mutation and the DNA aneuploidy was not statistically significant (p=0.38) 4. A p53 mutation by IHC or PCR-SSCP was more frequently detected in grade III breast cancers than in grade I or II. 5. Among 5 to 9 exons of the p53 gene, exon 7 was the most frequent mutation spot in this study. 6. Additional mutation of the p53 gene was developed in the three metastatic lesions. With the above results it is suggested that the p53 protein overexpression by immunohistochemistry is not correlated with the p53 mutation by PCR-SSCP. The p53 mutation pattern between the primary and metastatic lesions are not idenitical and an additional point mutation can occur in the metastatic lesion. The DNA aneuploidy is more frequently detected in the cases with the p53 protein overexpression than in the p53 protein negative, but it is not statistically significant.

Microvessel Quantitation and Assessment of its Utility by CD34 Staining in Invasive Breast Carcinoma.: Hwa Sook Jeong, Ro Hyun Sung; Korean J Pathol. 1997;31(4):298-307.

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Abstract PDF: Tumor angiogenesis, the development of new blood vessels by tumor, is a widely observed phenomenon associated with the growth of human solid tumors. To investigate how tumor angiogenesis correlates with other prognostic features i.e. menopause status, tumor size, lymph node metastasis, mitosis, angioinvasion, estrogen receptor (ER), p53 protein expression, histologic grade and clinical stage, we counted microvessels by immunohistochemistry using antibody for CD34 antigen in 56 cases of invasive breast carcinoma (27 with and 29 without axillary lymph node metastases) and 20 cases of non-inflammatory benign breast lesion. CD34 antigen is expressed on the surface of hematopoietic progenitor cells and more sensitively expressed than factor VIII in vascular endothelial cells. Microvessel count (MVC) was performed at a single hot field of 200x magnification (0.74 mm2 per field). The results are summarized as follows; 1) The mean MVC of invasive carcinoma and benign breast lesion were 92.0+/-54.4 (range, 7-237) and 20.7+/-16.6 (range, 4-73), respectively (p<0.0001). 2) Although MVC had no correlation with all other prognostic factors i.e. menopause status, tumor size, lymph node metastasis, mitosis count, angioinvasion, ER, p53 protein expression, histologic grade, and clinical stage (p>0.05), MVC had a tendency to increase in tumors with axillary LN metastasis or without ER expression. 3) Without correlation with MVC, ER (+), angioinvasion (-) and higher histologic grade correlate to significantly higher mitosis count (p<0.0005). Also, angioinvasion correlate to a significantly higher histologic grade (p<0.05). In conclusion, angiogenesis is related to tumorigenesis, but MVC may not be related to other clinicopathologic factors.

Expression of nm23 Protein in Breast Carcinoma: An immunohistochemical study.: Sang Yong Song, Je G Chi, Se Hwan Han, Kuk Jin Choe; Korean J Pathol. 1995;29(4):469-477.

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Abstract PDF: To elucidate a possible prognostic factor, we studied 91 cases of breast carcinoma for the expression of n-tn23 protein using an immunohistochemical method, and compared these results with the known prognostic parameters of the breast carcinoma. The mn23 protein was intensely stained in the cytoplasm and/or the nucleus of carcinoma cells in 82 cases(90.1%). There were two patterns of cytoplasmic staining; heterogeneous pattern and homogeneous pattern. Among the positive cases, 43 cases(47.2%) were heterogeneous while 39 cases(42.8%) were homogeneous. Axillary lymph node metastases(p<0.005) was found more frequently in the heterogeneous pattern group(79.0%) than in the homogeneous pattern group(41.0%). There was no significant correlation between nm23 protein expression and other parameters such as patient age, tumor size, estrogen receptor, histopathologic grade, and p53 overexpression. Although axillary lymph node metastasis was correlated with the disease free status(p<0.0005) and patient survival (p<0.05), they showed no correlation with nin23 expression. Multivariate analysis showed that axillary lymph node metastasis was the only prognostic indicator(p<0.05), and the expression of nm23 protein was of borderline significance. The results suggest that the homogeneous and/or granular cytoplasmic expression of mn23 protein plays a role in the suppression of nodal metastasis in breast carcinoma and might contribute in predicting patient survival.

Immunocytochemical Assay of Cathepsin D in Fine Needle Aspiration Cytology of Breast Carcinoma and Benign Breast Diseases .: Kyeongmee Park, Illhyang Ko; J Pathol Transl Med. 2000;11(2):75-81.

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Abstract PDF: Cathepsin D is a protease which is known to facilitate invasion and metastasis of breast carcinoma. Overexpression of cathepsin D is associated with poor clinical outcome and biologic aggressiveness of the breast cancer. We underwent immunocytochemical assay(ICA) for cathepsin D in fine needle aspiration cytology(FNAC) specimens from the breast carcinoma and benign breast diseases. In FNAC specimens cathepsin D was expressed in 21(42.9%) out of 49 cases of invasive ductal carcinoma, whereas negative result was observed in all 15 cases of benign breast diseases including 7 fibroadenomas, 6 fibrocystic diseases, and 2 benign ductal hyperplasias. Among the 11 FNAC specimens from ductal carcinoma in situ(DCIS), cathepsin D was expressed in 3 cases(27.3%). In FNAC specimens immunocytochemistry for cathepsin D showed positive result in 24 out of 60 carcinomas(sensitivity, 40%) and negative result in 15 out of all 15 benign breast diseases(specificity, 100%). No significant correlation was noted between cathepsin D expression in FNAC specimen and clinicohistological characteristics of the breast carcinoma, such as hormone receptors and cell differentiation. In conclusion, ICA of cathepsin D in FNAC specimens thought to be a good adjunct to differentiate malignancy from benign breast diseases.

Expression of p53 Protein and c-erbB-2 Oncoprotein in Breast Carcinoma.: Eun Hee Lee, Dong Sug Kim, Tae Sook Lee, Soo Jung Lee; Korean J Pathol. 1995;29(5):596-606.

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Abstract: This study was conducted to evaluate the expression of p53 and c-erbB-2 using immuno-histochemical methods in 145 primary breast carcinomas and to correlate it with other histo-pathological prognostic factors. Invasive ductal carcinoma represented 129 of the cases. Expression of p53 protein and c-erbB-2 oncoprotein was present in 48% (62/129) and 30% (39/129) of invasive ductal carcinomas, respectively. The expression of p53 protein was stongly associated with a high score of degree of differentiation (p<0.05), nuclear pleomorphism (p<0.05), mitotic index (p<0.05), SBR grade (p<0.05) and MSBR grade (p<0.05), but it was not associated with patient's age, size of tumor or axillary node metastasis. The overexpression of c-erbB-2 C-erbB-2 oncoprotein was strongly associated with a high score of nuclear pleomorphism and a high SBR grade (p<0.05), but not associated with patient's age, size of tumor, axillary node metastasis, degree of differentiation, mitotic index or MSBR grade. An inverse relationship between the expression of p53 protein and estrogen receptor status was found, but the expression of c-erbB-2 was not associated with estrogen receptor status. It is concluded that p53 protein and c-erbB-2 oncoprotein are important prognostic factors in breast cancers, and that the aberrant expression of p53 protein is the most useful prognostic factor becausd of strong association of known histopathological prognostic factors and negative estrogen receptor status.

Case Report

Infiltrating Ductal Carcinoma of the Breast with Stromal Osteoclast-Like Multinucleated Giant Cell: A case report.: So Ya Paik, Sang Yeop Yi, Jai Hyang Go, Dong Hwan Shin; Korean J Pathol. 1996;30(1):61-64.

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Abstract PDF: Malignant tumors of the breast which contain stromal osteoclast-like, multinucleated giant cells are a rare entity of yet unknown clinical significance. These benign multinucleated giant cells are known to occur mostly in areas of prominent angiogenesis and in close association with tumor cells. Supplementary immunohistochemical and electronmicroscopic examinations indicate that the multinucleated giant cells are of histiocytic origin. We report on a case of infiltrating ductal carcinoma with stromal osteoclast-like multinucleated giant cells occurring in the right breast of a 37 year-old woman. Grossly, the tumor was characterized by a well-circumscribed dark brown, solid firm mass. Microscopically, multinucleated giant cells were found in the stroma intermingled with malignant tumor cells. The stroma showed only a small amount of mononuclear cell infiltration and a moderate degree of vascular proliferation. Immunohistochemical stains revealed the tumor cells to be positive for carcinoembryonic antigen, epithelial membrane antigen and cytokeratin while the multinucleated giant cells were positive for vimentin, CD68 and negative for all other stains tested. Ultrastructurally the multinucleated giant cells differed from tumor cells by having abundant cytoplasmic organelles such as rough endoplasmic reticulum, lysosomes, ribosomes, and vesicles but lacking desmosomes or other types of intercellular junctions. Other characteristic features of multinucleated giant cells included, indented nuclei and prominent cytoplasmic process.

Original Articles

Clinical Value of Demonstration of Estrogen and Progesterone Receptors using Paraffin Wax Sections in Breast Carcinoma.: Hye Kyung Ahn, Yun Jung Kim, Young Euy Park; Korean J Pathol. 1996;30(2):89-93.

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Abstract PDF: This study aimed at assessing the usefulness of paraffin wax sections for demonstration of ER(estrogen receptor) and PR(progesterone receptor), using brief microwave processing rather than proteolytic predigestion. The receptor status of a breast cancer is often into consideration when planning treatment nowadays. As biochemical receptor assays require large amount of fresh tumor tissue and are not always available for all tumors, pathologists are now increasingly asked to provide a service for the assessment of the receptor status in tissue routine sections. Until recently, immunohistochemical demonstration of receptors was used in frozen sections. Therefore, routinely processed paraffin wax sections of 25 cases of breast carcinoma with known ER and PR concentrations, estimated by the standard DCC(dextran-coated charcoal) biochemical assay, were examined using the ABC immunoperoxidase technique. The results were assessed semiquantitably, using a five grade scoring system. Of the 25 cases examined, with DCC cutoff point being <10 fmol,71% and 75% in positivity of each ER, PR receptor is concordant. Statistic analysis demonstrates high relationship between scoring system of IH method and DCC value in ER (R=0.6061, p=0.001) and PR (R=0.5832, p=0.001). The IH method can provide easily assessed reliable positive information about ER, PR status of breast carcinoma using routinely processed paraffin wax sections.

Estrogen Receptor Analysis in Fine Needle Aspirates and Frozen Sections from Human Breast Carcinomas.: Gyung Yub Gong, Se Hyun Ahn, Kun Choon Park, Ghee Young Choe, Eun Sil Yu, In Chul Lee; J Pathol Transl Med. 1994;5(1):10-14.

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Abstract PDF: The expression of sex steroid hormone receptors by neoplastic cells is an important predictor of response to hormone therapy. Thus, the selection of treatment modality is often based on the identification of receptors in tumor tissue. Various monoclonal antibodies of high specificity are now available for analyzing the estrogen receptor(ER). With these antibodies, biochemical enzyme immunoassay and immunohistochemistry using histologic sections have been used for ER analysis. We used fine needle aspirates from 15 human primary breast carinomas for the analysis of ERs. The semiquantitative receptor values obtained in cytologic specimens were correlated well with those from histologic specimens. The results of ER in fine needle aspirates were concordant with ER in histologic specimens(r=0.94). Only three cases showed a little difference in staining intensity and proportion of positive cells. Our results showed a good correlation between the receptor values determined in cytologic smears and those determined in tissue sections. It is suggested that measurement of the ER in cytologic smears may be a reliable technique which can be performed on aspiration cytologic samples.

E-Cadherin Expression in Breast Carcinoma: Correlation with Tumor Grade and Hormone Receptor.: Haeng Ji Kang, Chan Pil Park, Chan Kum Park; Korean J Pathol. 1997;31(11):1172-1179.

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Abstract: E-cadherin (E-CD), a Ca2+ -dependent adhesion molecule, plays a major role in the maintenance of intercellular junctions in normal epithelial cells in most organs. Recently, a correlation has been observed between a loss of E-CD and increased invasiveness of neoplastic cells. In this study, E-CD expression in the breast carcinoma was investigated using monoclonal antibody, anti-E-CD by immunohistochemical method. Expression of E-CD were evaluated in 57 breast carcinomas and correlated with their tumor grade, lymph node involvement, and hormonal receptor status. Histological types included in this study were 54 invasive ductal carcinomas (IDCs) of otherwise not specified and 3 invasive lobular carcinomas. Cases of histologic grade I IDC were 6, grade II 30, and grade III 18. Of 54 IDCs 39 (72.2%) showed moderate to strong linear staining at the cell borders regardless of their histologic grade, status of lymph node metastasis, and status of hormone receptor. Staining intensity of E-CD was reduced in 54 cases (83%) of IDC when compared with that of normal or benign breast lesions (P<0.01). All seven cases of intraductal carcinoma, which were included in 54 IDCs showed one or two grade reduced expression of E-CD than that of infiltrative lesions. Three invasive lobular carcinomas showed strong (1 case), moderate (1 case), and negative reactivity (1 case). The data indicated that loss of E-CD expression is a crucial event in the development of breast carcinoma.

Expression of the nm23 and E-cadherin Proteins in Breast Carcinoma.: Jean a Kim, Won Il Kim, Sang In Shim, Chang Suck Kang, Kyo Young Lee, Young Shin Kim; Korean J Pathol. 1998;32(1):29-34.

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Abstract PDF: Expression of the nm23 and E-cadherin proteins has been studied in a number of tumors. Reduced expression of the nm23 and E-cadherin proteins seems to be associated with metastasis or disease progression in some tumors, including breast carcinoma. To assess the role of nm23 and E-cadherin in tumor differentiation and metastasis of breast carcinoma, immunohistochemical staining for the nm23 and E-cadherin proteins was performed in paraffin embedded tumor samples from 86 breast carcinomas. The results were as follows: 1) Expression of the nm23 protein in breast carcinoma was strong positive in 32 cases (37.2%), weak positive in 26 cases (30.2%), and negative in 28 cases (32.6%) of the cases. Expression of the nm23 protein in breast carcinoma decreased according to histological grade and lymph node metastasis, but was not statistically significant. 2) Expression of the E-cadherin protein in breast carcinoma was strong positive in 50 cases (58.1%), weak positive in 24 cases (27.9%), and negative in 12 cases (14%) of the cases. Expression of the E-cadherin protein in breast carcinoma decreased according to histological grade and lymph node metastasis, but was not statistically significant. 3) There was a statistically significant correlation between the expression of the nm23 protein and the E-cadherin protein in breast carcinoma (p<0.05). These results suggest that the expression of the nm23 and E-cadherin proteins is related to tumor differentiation, and may also be an useful prognostic factor in breast carcinoma.

p 53 Protein Expression in Imprint Cytology of Breast Carcinoma.: Dong Sug Kim, Eun Hi Lee, Ki Kwon Kim, Mi Jin Kim, Soo Jung Lee; J Pathol Transl Med. 1995;6(1):1-9.

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Abstract PDF: This study was carried out to determine the usefulness of imprint cytology for detecting p 53 protein in breast carcinoma. NCL-DO7(Novocastra, U.K.) was used to detect p53 protein immunocytochemically. A total of 33 cases was studied. Immunostaining of imprint cytology with NCL-DO7 was positive in 64%(21\33) and showed relatively high coincident rate (80 %) with immunostaining of formalin-fixed, paraffin - embedded specimen. p 53 protein was related to negative estrogen receptor status, but not to the nuclear grade, lymph node metastasis, or tumor size. The fact that p53 protein expression was not related to nuclear grade might be due to predominance of nuclear grade 3. It was easier to determine the nuclear grade is one of the most important prognostic factors, in imprint cytology than in tissue specimen. p53 protein tended to be stained more strongly in imprint cytology than in tissue.

Cytologic Findings of Breast Carcinoma in Fine Needle Aspiration: Comparison with Histologic Findings, Stage and Lymph Node Metastasis.: Hee Jin Chang, Duck Hwan Kim, Sung Sook Paeng, Sung Eun Yang, Jin Hee Sohn, Jung Il Suh, Hyo Sook Park; J Pathol Transl Med. 1995;6(1):18-26.

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Abstract PDF: In order compare cytologic findings of breast carcinoma in fine needle aspiration cytology (FANC) with histologic findings and prognostic factors including histologic grading, lymph node metastasis and stage, 79 cases of infiltrating ductal carcinoma diagnosed by FANC and confirmed by histology were analysed. We especially attempted to correlate nuclear grade, cellularity and smear pattern with histologic grade, type, status of lymph node metastasis and stage. The results are as follwos : 2. Individual cell pattern was more frequently identified in high histologic grade and scirrhous or solid-tubular type than in low histolgic grade and papillotubular type. 3. Cellularity increased with higher histologic grade and lymph node metastsis. However cellularity was low in scirrhous type. 4. There is no relationship between nuclear grade and histologic type, between smear pattern and lymph node metastasis or stage, and between cellularity and stage. These results suggest that cytologic findings of breast carcinoma such as nuclear grade, cellularity and smear pattern are indicative of histologic findings in relation to histolgic grade and type. Especially, nuclear grade of FANC may yield valuable prognostic information.

Expression of Vascular Endothelial Growth Factor-C in Breast Carcinoma.: Myoung Ja Chung, Sun Ho Yang, Kyu Yun Jang, Woo Sung Moon, Myoung Jae Kang, Dong Geun Lee; Korean J Pathol. 2005;39(6):401-405.

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Abstract PDF: BACKGROUND
Vascular endothelial growth factor-C (VEGF-C) is a novel growth factor that regulates lymphangiogenesis and/or angiogenesis via binding to the vascular endothelial growth factor receptor-3 (VEGFR-3) or VEGFR-2. Recent studies have suggested that VEGF-C may play a role in lymph node metastasis. This study was conducted to examine whether the expression of VEGF-C is associated with the clinicopathologic parameters, and especially lymph node metastasis, of invasive ductal carcinoma.
METHODS
Immunohistochemical staining was performed for VEGF-C and CD31 in the surgically resected specimens from 83 patients with invasive breast carcinoma.
RESULTS
Of the 83 breast carcinomas, 61 (74%) cases showed cytoplasmic VEGF-C imunoreactivity. VEGF-C expression was associated with lymph node metastasis (p=0.03), but it did not correlate with tumor size, the histologic grade, and the presence of estrogen receptor or progesteron receptor. The mean microvessel density in the cases without VEGF-C expression was 51.9+/-30.1 and it was 72.9+/-33.0 in the cases with 2+ expression for VEGF-C (p=0.07).
CONCLUSIONS
This study suggests that VEGF-C expression may have an association with lymph node metastasis in the patients with breast carcinoma.

The Relation between Cell Proliferation and Apoptosis According to the Histologic Types in Chemically Induced Rat Mammary Tumorigenesis.: Tae Jung Jang, Woo Hee Jung, Kwang Gil Lee; Korean J Pathol. 1998;32(3):174-185.

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Abstract PDF: Balancing the rates of cell proliferation and cell death is important in maintaining normal tissue homeostasis. The relationship among apoptosis, cell proliferation and factors influencing apoptosis according to the histologic types in chemically induced mammary tumorigenesis appears important in understanding the pathogenesis of breast carcinoma. In this study, we investigated alterations in the kinetics of cell proliferation and apoptosis during rat mammary tumorigenesis induced by 7, 12-dimethylbenzanthracene (DMBA) and we related these changes to the expressions of bcl-2, p53, and TGF-beta. Seven-week-old female Sprague-Dawley rats were divided into an experimental group (20 mg/ml DMBA by oral intubation) and a control group. The results were as follows. 1. In the experimental group, breast tumors occurred in twenty two of fifty nine rats(37.3%, 22/59), and the total number of tumors was 100 (4.5 2.0/rat). The histological classification was infiltrating ductal carcinomas (n=5), ductal carcinomas with focal invasion (n=10), intraductal carcinomas (n=36), adenomas accompanied with intraductal proliferation (n=35), intraductal proliferation (n=9), and adenomas (n=5); 2. The differentiation of terminal end bud into alveolar bud (AB) in the experimental group was significantly lower than that of the control group (p<0.05); 3. BrdU labeled tumor cells were mainly located at the peripheral portion of tumor cell nests. BrdU labeling indices were highest in ductal carcinomas, less pronounced in intraductal proliferation, and lowest in adenomas, whereas apoptosis levels were highest in adenomas, less pronounced in intraductal proliferation, and lowest in ductal carcinomas (p<0.05); 4. p53 protein was not expressed in any breast tumors. Although the expression of bcl-2 protein was highest in infiltrating and focal infiltrative ductal carcinomas (58.3%), compared with adenomas, intraductal proliferation, and intraductal carcinomas (p<0.05), the extent of its expression was less than 1% of all tumor cells; 5. TGF-beta was mainly expressed in the central portion of tumor cell nests rather than in peripheral portion, and TGF-beta immunoreactive tumor cells displayed good differentiation and did not reveal BrdU immunoreactivity. TGF-beta labeling index of infiltrating and focal infiltrative ductal carcinomas was significantly higher than that of intraductal carcinomas, intraductal proliferation, and adenomas (p<0.05). Based on these results, it is thought that high cell proliferation and the suppression of apoptosis are closely associated with DMBA-induced rat mammary carcinogenesis. However, the suppression of apoptosis is not related to p53 mutation, bcl-2, and TGF-beta. TGF-beta seems to be reversely related to tumor cell proliferation but closely associated with the progression of the tumor, especially an invasion of breast carcinomas.

Microvessel Density and Vascular Endothelial Growth Factor Expression in Invasive Breast Carcinomas.: Mi Yeong Jeon, Mee Young Sol, Kyung Sun Park, Hye Kyoung Yoon; Korean J Pathol. 2000;34(2):138-144.

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Abstract PDF: Angiogenesis is essential for tumor growth and metastasis, however, the prognostic value of neovascularization is undetermined. The aim of this study is to evaluate the prognostic significance of microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression in breast carcinomas. An immunohistochemical stains for CD 31 (DAKO) to estimate MVD and VEGF (Santa Cruz) were done on 40 cases of invasive breast carcinoma. MVD was calculated as an average count of vessels per 200 power field in the most vascularized areas. VEGF expression was interpreted according to staining intensity and number of positive cells. Mean MVD was 35, and MVD was not correlated with lymph node metastasis or histologic grade, but high MVD (mean MVD>35) showed an increasing tendency in cases with larger size, negative ER/PR, and positive cathepsin D. All of the cases showed VEGF expression, but VEGF expression was not correlated with tumor size, histologic grade, lymph node metastasis, ER/PR status, and cathepsin D expression. These results suggest that MVD and VEGF expressions are not reliable prognostic factors.

Cyclin D1 Expression in 101 Cases of Breast Carcinoma.: Duck Hwan Kim, Eun Sook Nam, Hyung Sik Shin, Jin Woo Ryu, Jai Hyang Go, Young Lyun Oh, Sang Yong Song, Dae Shick Kim, Min Chul Lee; Korean J Pathol. 1998;32(4):266-272.

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Abstract PDF: Cyclin D1, a cell cycle regulator essential for G1 phase progression, is a candidate proto-oncogene implicated in pathogenesis of several human carcinomas including breast carcinoma. We studied the cyclin D1 expression in 101 cases of primary breast carcinoma tissues. The overexpression of cyclin D1 was immunohistochemically demonstrated in 34 (37.8%) of 90 cases of invasive breast carcinoma. Positive cyclin D1 staining was seen in 32 of 79 invasive ductal carcinomas, and 2 of 3 mucinous carcinomas. All 5 medullary carcinomas, 2 invasive lobular carcinomas, and 1 metaplastic carcinoma were negative. Cyclin D1 overexpression was observed in 9 of 11 ductal carcinoma in situ (DCIS). Normal epithelial components, either ductal or lobular, were not immunoreactive for cyclin D1. No significant correlations were observed between cyclin D1 immunoreactivity and other parameters including tumor size, clinical stage, nuclear or histologic grades, lymphatic or angioinvasion, lymph node metastasis, and immunohistochemical status of progesterone receptor, p53 and c-erbB-2. The overexpression of cyclin D1 was positively correlated with estrogen receptor status (p=0.025). Based on our results, the cyclin D1 protein aberration may play a role in tumorigenesis of breast carcinoma, but does not seem to have prognostic value in invasive breast carcinoma without hormonal treatment.

Expression of p53, bcl-2 Proteins and Estrogen Receptors in Human Breast Cancer.: Hee Kyung Chang, Choong Han Lee, Man Ha Huh; Korean J Pathol. 1996;30(8):662-670.

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Abstract PDF: In 56 breast cancer tissues (infiltrating ductal carcinoma) with a clinical follow-up period of more than 5 years, positivity of estrogen receptor(ER) by enzyme immunoassay and expressions of bcl-2 and p53 oncoproteins by immunohistochemistry were evaluated. The purposes of this study were to determine prevalence of bcl-2 and p53 in breast cancer, the interrelationship between expression of the proteins and estrogen receptor, correlation between histologic grade and the expression of the tumor-related oncogenes, and to explore the biologic bahavior of breast cancer (lymph node metastasis, recurrence rate, and survival) via expression of bcl-2 and p53. Twelve of 56 (21.4%) carcinomas were bcl-2 positive, and seventeen (30.4%) were p53- positive. Eleven of 12 bcl-2 positive tumors (91.7%) were ER-positive, and bcl-2 expression was significantly associated with ER-positivity(P=0.043). Seven of 36 ER-positive tumors (12.5%) were p53 positive, and p53 expression was inversely associated with ER-positivity(P=0.006) significantly. The bcl-2 protein expression showed a significant relationship to low histologic grade of tumor (P=0.0002), and an almost significant relationship to lower recurrence rate (P=0.09). The p53 protein expression showed a significant relationship to high histologic grade of tumor (P=0.002) and an almost significant relationship to lymph node metastasis (P=0.09). Also an almost inverse relationship between bcl-2 and p53 was demonstrated (P=0.057). The bcl-2 expression had a tendency to be associated with longer patient survival(P= 0.09), but p53 immunoreaction was found not to be associated with shorter patient survival(P=0.16). These results provide further evidence that higher incidence of bcl-2 expression is correlated with higher incidence of ER and lower grade of tumor, while p53 expression is correlated with lower incidence of ER and higher grade of tumor. In conclusion, although the biologic function of bcl-2 protein is not yet well understood in breast cancer, our results suggest that bcl-2 and p53 oncoproteins might play significant roles in estrogen receptor and development of breast cancer. But their prognostic significance could not be determined; our results are 'not significant' but 'almost significant'. Thus, contribution of bcl-2 and p53 immunohistochemical phenotyping of breast cancer with ER to the clinical management need verification in larger series.

Significance of Expression of p16, Cyclin D1, Rb, and p53 Protein and Correlation with Clinicopathologic Prognostic Factors in Invasive Ductal Carcinoma of the Breast.: Mi Ja Lee, Ho Jong Jeon, Kweon Cheon Kim; Korean J Pathol. 2000;34(4):288-299.

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Abstract PDF: The retinoblastoma (Rb)/cyclin D1/p16 pathway is an important constituent of cell cycle regulation. Perturbations in this pathway due to a variety of genetic aberrations have been reported in many human cancers including breast cancer. We examined the significance of immunoexpression of p16 protein, cyclin D1 protein, Rb protein (pRb), and p53 protein in 128 cases of invasive breast carcinoma. The results were correlated with survival rate and clinicopathological variables, including age, histologic grade, lymph node status, tumor size, estrogen receptor (ER), and progesterone receptor (PR) content. Abnormal expressions of p16 and pRb which were defined as negative staining were seen in 21% and 43% of tumors, respectively. There was a significant inverse relationship between p16 and pRb expression. There was no correlation between p16 staining and any other parameters, including survival rate, cyclin D1, p53, and clinicopathologic variables. Surprisingly, there was a trend for tumors which were positive for pRb to be grade III ductal carcinomas. Cyclin D1 positivity was noted in 46% of cases. The expression of cyclin D1 protein was significantly higher in lower histologic grade, higher ER and PR expression. The expression of p53 protein showed a significant correlation with high tumor grade. In a Cox multivariate analysis, neither p16, pRb, cyclin D1 nor p53 was an independent predictor, but tumor size and lymph node status were independent predictors of patient outcome.

Expression of Androgen Receptor, bcl-2 Protein and Rb Protein in Breast Cancers as Related to Prognostic Factors.: Hyun Deuk Cho, Young Sik Kim, Insun Kim; Korean J Pathol. 1998;32(6):443-452.

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Abstract: Breast cancer is the most common malignancy of women in industrialized countries and the third in Korean women. There have been a lot of studies on biologic behaviors as well as on the prognostic factors of the breast cancer. In this study, the expression of hormone receptors (estrogen receptor ; ER, progesterone receptor ; PR, and androgen receptor ; AR), bcl-2 and Rb proteins were immunostained on 60 infiltrating ductal carcinomas of the breast. The results were evaluated in relation with the age, histologic grade, tumor size, and status of lymph node metastasis. The expression of ER and PR had a significant inverse correlation with the histologic grade (p<0.001). The expression of AR was significantly correlated with the expression of ER (p=0.039) and PR (p=0.009), but not with other factors such as age, histologic grade, tumor size, and status of lymph node metastasis. There was no relationship between bcl-2 protein expresssion and other prognostic factors, except with the expression of ER. Rb protein expression had a significant positive relationship with PR (p=0.05) and the degree of positivity was correlated with histologic grade (p=0.002). In conclusion, this result suggests that expression of AR is well correlated with ER and PR. bcl-2 has no prognostic value. The significance of Rb protein expression remained to be studied.

Comparative Study

Comparative Study of the Breast Carcinoma by the Measurement of Nucleolar Organizer Regions and the Flow Cytometric DNA Analysis.: Ki Jung Yun, Weon Cheol Han, Chan Choi, Hyung Bae Moon; Korean J Pathol. 1992;26(2):117-124.

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Abstract PDF: It is important to predict the prognosis of patient with cancer. Well known parameters predicting the prognosis are staged and degree of differentiation. Recently, the prognostic and diagnostic significance of silver-stained nucleolar organizer regions(Ag-NORs) and flow cytometric DNA analysis are introduced. This study aims to detect the diagnostic significance of Ag-NORs in breast lesions, and to correlate the number of Ag-NORs and cellular ploidies in breast carcinoma. In addition, the existence of heterogeneity according to the sample in the same patient is studied Sixty six paraffin blocks(two primary lesions and the two metastatic lymph nodes in 13 patients, and one primary lesion and one metastatic lymph node I 10 patients) of breast carcinoma, 30 paraffin blocks of fibroadenoma and 23 paraffin blocks of normal breast are studied. The numbe of Ag-NORs increase from normal breast(mean 1.45) through fibroadenoma(mean 1.60) to carcinoma(mean 2.43). It was significantly different between each lsions(P<0.0005). The number of Ag-NORs increased in the aneuploidy carcinoma than that in the euploidy one(P<0.05). But, there was difference between the number of Ag-NORs and DNA index according to the sample area in the same patient with carcinoma. In conclusion, the number of Ag-NORs is diagnostically significant in breast lesions and is correlated with cellular ploidies in breast carcinoma. In addition, Ag-NORs and cellular ploidies are heterogenous in the same patient.

Original Articles

Correlation of Heregulin mRNA and Her-2/neu Protein Expression with Node Metastasis and DNA Ploidy Pattern in Human Invasive Breast Carcinoma.: Yee Jeong Kim, Woo Hee Jung, Hyde Lee, Sung Kong Lee, In Gul Moon, Kwang Gil Lee; Korean J Pathol. 1998;32(8):563-573.

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Abstract: The Her-2/neu protooncogene encodes a transmembrane tyrosine kinase that is structurally homologous to the receptor for epidermal growth factor. Its amplification and overexpression are associated with poor prognosis in breast cancer patients. Neu differentiation factor is a ligand for Her-2/neu protooncogene and was detected in ras-transformed rat fibroblasts. Heregulin (human homologue of neu differentiation factor) is a 44-kilodalton glycoprotein that stimulates tyrosine phosphorylation and induces growth arrest or stimulation and differentiation in human breast cancer cell lines. In this study we examined the expression of heregulin mRNA by nested reverse transcription (RT) PCR with fresh tissue, Her-2/neu protein, ICAM-1 and steroid receptors by immunohistochemistry, and DNA ploidy pattern by flow cytometry with paraffin-embedded tissue in invasive breast carcinoma. We compared the data with nodal status, lymphovascular invasion, steroid receptor status and DNA ploidy pattern. For RT-PCR to heregulin mRNA, 38 cases of fresh breast cancer tissue were obtained. Total 68 cases of invasive breast carcinoma tissue were fixed in formalin, which were used for routine histology, immunohistochemistry and flow cytometry. The results are as follows; 1) Heregulin mRNA was expressed in 86.1% of patients with invasive breast carcinoma and 100% of patients with benign breast lesion using nested RT-PCR analysis. 2) Her-2/neu protein was overexpressed in 50.0% of tumors using immunohistochemistry. The expression of Her-2/neu protein was significantly correlated with high counts of lymph nodes with metastasis (p<0.05), and high nuclear grade (p<0.05). 3) Her-2/neu protein overexpression was significantly correlated with a high DNA index(p<0.05). All of the tumors showing Her-2/neu protein overexpression and no heregulin mRNA expression revealed near tetraploid DNA content. However, both Her-2/neu overexpression and heregulin mRNA expressing tumors revealed near tetraploidy in 38.9% and diploidy in 50.0%. Based on these results, heregulin mRNA expression rate was 86.1% in human invasive breast carcinoma. Her-2/neu protein overexpression is associated with high positive lymph node number and DNA index. Statistically significant reverse correlation with lymph node metastasis is not present.

Flow Cytometric DNA Content Analysis in Breast Cancer Comparison study of fresh and paraffin-embedded tissues.: Jin Ye Yoo, Hye Jae Cho; Korean J Pathol. 1998;32(11):993-999.

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Abstract: DNA content of 25 cases of breast carcinoma was analyzed by flow cytometry in both fresh and formalin-fixed, paraffin-embedded tissue. Aneuploidy in fresh tissue and paraffin-embedded tissues was 72% and 32%, respectively. There was a 52% agreement in analysis of DNA ploidy between fresh and paraffin-embedded tissues. Most of the discrepancies resulted from loss of aneuploid peaks on the histograms of paraffin-embedded tissue. Mean S-phase fraction was slightly higher in a paraffin-embedded tissue than that in the fresh tissue; 19.2 9.1% versus 16.1 8.8% and there was no significant correlation between the S-phase fractions. In statistical analysis, the histologic and nuclear grades were not correlated with ploidy or mean S-phase fraction. Therefore it is strongly recommended to use the fresh tissue in flow cytometric DNA content analysis of breast cancer.

A Study of the Correlation between Expression of c-erbB-2 Oncoprotein and Various Clinicopathological Prognostic Factors in Breast Carcinoma.: Jong Hee Nam, Kyung Soo Kim, Chang Soo Park, Sang Woo Juhng; Korean J Pathol. 1995;29(2):136-144.

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Abstract PDF: Immunohistochemical study for c-erbB-2 oncoprotein was performed on paraffin sections of 76 primary breast carcinomas to determine the relationship between expression of c-erbB-2 and various clinicopathological prognostic indicators, including the expression of epidermal growth factor receptor (EGFR). Positive reaction for c-erbB-2 oncoprotein revealed an intense red granular staining predominantly located at the tumor cell membrane, with some cells exhibiting a weak cytoplasmic staining as well. The epithelial cells of the normal lobule and duct showed a negative reaction. Positive reaction for EGFR revealed a granular staining in the cytoplasm and the cell membrane of the tumor cells. Some tumors showed a positive EGFR staining in the epithelial cells of normal duct and lobule. Twenty six of 76 cases (34.2%) of primary breast carcinomas revealed a positive reaction for c-erbB-2 oncoprotein, and 28 cases (36.8%) were positive for EGFR. Expression of c-erbB-2 oncoprotein and EGFR was evident in 37.7% and 40.6% of 69 classic invasive ductal carcinomas, respectively. None of the other histological types showed a positive reaction. Expression of c-erbB-2 oncoprotein was strongly associated with tumor size(p=0.0015), histologic grade(.p=0.0175), vascular invasion(p=0.0043), and lymph node metastasis(p=0.0024), but not with age at diagnosis(p=0.1836). No significant association was found between expression of c-erbB-2 oncoprotein and EGFR. Co-expression of c-erbB-2 oncoprotein and EGFR was also strongly associated with tumor size (p=0.0029). These results suggest that c-erbB-2 oncoprotein is biologically distinct from EGFR, and may be used as a prognostic indicator of breast carcinoma due to its strong association with various clinicopathological prognostic factors.

A Histopathological Study on the Estrogen-induced Breast Lesion in Rats.: Gyung Hyuck Ko, Cheol Keun Park, Myoung Keun Shin, Soo Min Kang, Hye Jung Lee, Jeong Hee Lee; Korean J Pathol. 1992;26(5):466-475.

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Abstract PDF: Forty eight female Sprague-Dawley rats received a subcutaneous implant containing 12.5 mg estradiol ant the age of 3 weeks. Three rats were killed in 1, 2, 3, 4, 6 weeks and in every month during 2~12 months after implantation, and the breasts were examined by light microscope. In all rats, enlargement of terminal end buds was obseved in 1~2 weeks, maximum development of hyperplastic alveolar nodules in 3 weeks, and marked dilatation and secretion of alveoli or ducts in 1~12 months after implantation. Ductal epithelial hyperplasia was observed in 27 rats and carcinomas developed in 23 rats in 2~12 months after implantation. It was thought that the changes induced by estradiol are more similar to the human breast lesions, compared with changes induced by chemical carcinogens such as dimethylbenzanthracene(DMBA), because breast carcinomas developed in close relationship with ductal epithelial hyperplasia in both estradiol-treated rats and humans, but not in DMBA-treated rats.

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