Journal of Pathology and Translational Medicine

Volume 34(4); April 2000

Original Articles

Expression of Matrix Metalloproteinase and Tissue Inhibitors of Matrix Metalloproteinase in Malignant Lymphoma.: Ah Won Lee, An Hi Lee, Chang Suk Kang, Byung Kee Kim; Korean J Pathol. 2000;34(4):249-256.

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Abstract PDF: Matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of matrix metalloproteinases, TIMPs) play essential roles in the remodelling of the extracellular matrix. The balance between MMPs and TIMPs is altered in neoplasia, contributing to the invasive and metastatic properties of malignant tumors. Although MMP and TIMP are believed to play an important role in invasion and metastasis in malignant solid tumors, little is known about their involvement in malignant lymphoma. Immunohistochemical stains for MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2 were performed using 56 paraffin blocks of the malignant lymphoma and the results were analyzed by using the tumor grade by Working Formulation. The expression of MMP-9 was noted in 45.5% of low grade, 86.1% of intermediate grade, and 100% of high grade malignant lymphoma. The incidence of MMP-9 expression in tumor cells was positively correlated with the grade of the malignant lymphoma (P<0.025). In nodal lymphomas, the incidence of the MMP-9 expression of the tumor cells was higher in malignant lymphoma with extracapsular invasion than those without extracapsular invasion (P=0.008). The incidence of TIMP-1 expression in the tumor cells and fibroblasts was positively correlated with the grade of the malignant lymphoma (P<0.025). In nodal lymphoma, the incidence of the TIMP-1 expression of the tumor cells was higher in malignant lymphoma with extracapsular invasion than those without extracapsular invasion (P=0.009). The incidences of the MMP-1, MMP-2, and TIMP-2 expression in malignant lymphoma were neither increased in the malignant lymphoma with extracapsular tumor invasion nor correlated with the grade by working formulation. There was no significant difference in the expression rate of MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 in nodal- and extra-nodal malignant lymphoma. The above results suggest that the expressions of MMP-9 and TIMP-1 are positively correlated with the grade and the presence of extranodal tumor invasion in malignant lymphomas.

Argyrophilic Nucleolar Organizer Region and Expression of Ki-67 in Malignant Lymphoma.: Hee Jung Lee, An Hi Lee, Kyo Young Lee, Chang Suk Kang, Sang In Shim, Byung Kee Kim; Korean J Pathol. 2000;34(4):257-263.

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Abstract PDF: Nucleolar organizer regions (NORs) are loops of DNA which occur in the nucleoli of cells which possess ribosomal RNA genes. The numbers and areas of NORs have been thought to be related to cellular activities. We aimed to investigate the direct relationship between the parameters of AgNORs and cellular proliferative activity using immunohistochemical method with the monoclonal antibody Ki-67, which demonstrates proliferating nuclei. The sequential technique for the simultaneous Ki-67 immunostaining and NOR staining was applied to the same slides of a series of non-Hodgkin's lymphomas (NHL) of the low, intermediate, and high grade type. The number of AgNOR per cell was counted and mean NOR percentage nuclear area (NPNA) was measured by morphometry in both the Ki-67 positive and Ki-67 negative nuclei. The increased immunoreactivity for Ki-67 was found in the high grade than in the low grade non-Hodgkin's lymphoma. This was reflected in the two areas of the palatine tonsils and lymph nodes, the positive cell counts being higher in the follicle center nuclei than in those in the interfollicular compartment. In general the numbers and NPNA of AgNORs were higher in the Ki-67 positive nuclei than in those lacking the antigen in malignant lymphomas as well as in control. The AgNORs numbers and NPNA in controls were the highest in the Ki-67 positive cells in the follicular area and the lowest in the Ki-67 negative cells in the perifollicular area. In malignant lymphomas the numbers and NPNA of AgNORs tended to increase in proportion to their grade in both the Ki-67 positive and negative cells. The numbers of AgNORs of the high grade and the NPNA of the intermediate and the high grade were significantly higher in Ki-67 positive cells than in Ki-67 negative ones. With this double staining method it was now possible to confirm that numbers and NPNA of AgNORs were directly related to the cellular proliferative activity. In maligant lymphoma, among the several parameters of the AgNORs, NPNA in Ki-67 positive cells is proposed to be the most useful marker in determining the prognosis of the patient.

Correlation of Expression of E-Cadherin, alpha-Catenin, beta-Catenin, and Clinicopathologic Parameters in Colorectal Adenocarcinomas.: Hyoung Joong Kim, Tae Jin Lee, Eon Sub Park, Jae Hyung Yoo; Korean J Pathol. 2000;34(4):264-272.

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Abstract PDF: The E-cadherin, alpha-catenin, and beta-catenin expressions were immunohistochemically investigated in paraffin-embedded materials of 80 cases of colorectal adenocarcinomas. The staining similar to normal colorectal mucosa with preserved strong membranous staining pattern was considered normal or preserved expression. The X2 test was used to analyse the statistical correlation of cadherin/catenin expression with clinicopathologic parameters and the Breslow test for the correlation with survival length. Normal colorectal mucosa showed strong membranous expression of cadherin/catenin complex. The reduced E-cadherin, alpha-catenin, and beta-catenin expression were found in 53/80 (66.3%), 46/80 (57.5%), and 44/80 (55.5%) cases of colorectal cancers examined, respectively. There were significant correlations between E- cadherin and alpha -catenin (p=0.035), and between alpha-catenin and beta-catenin (p=0.013). The reduced E-cadherin expression was associated with histologic dedifferentiation, tumor depth, lymph node metastasis, clinical stage (p<0.05), poor clinical outcome in stage II (p=0.016) and the reduced alpha-catenin expression with lymph node metastasis and clinical stage (p<0.05). Reduced expression of two or more proteins was correlated with lymph node matastasis, histologic dedifferentiation, clinical stage, and survival (p<0.05). The present study demonstrates a significant down-regulation of E-cadherin and alpha-catenin expression in colorectal cancer is associated with tumor invasiveness, histologic dedifferentiation, lymph node metastasis, and clinical stage. These results suggest that E-cadherin and alpha-catenin may be useful markers of invasiveness, lymph node metastatic potential, and clinical stage and of value as prognostic markers in the earlier stage. Further studies are needed to confirm the prognostic value of these cadherin/catenin complex.

Epidermal Growth Factor Receptor Expression and Cell Proliferation in Renal Cell Carcinoma.: Ji Shin Lee, Jong Jae Jung, Min Cheol Lee, Chang Soo Park; Korean J Pathol. 2000;34(4):273-279.

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Abstract PDF: The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein whose expression is a possible cause of increased tumor cell proliferation and has recently been proposed as a prognostic parameter in some tumors. Expression of EGFR was studied immunohistochemically in 62 cases of human renal cell carcinomas to evaluate their possible prognostic roles. We also examined the correlation between EGFR expression and cell proliferation by immunohistochemical staining for proliferating cell nuclear antigen (PCNA). Fifty-six cases (90.3%) expressed EGFR, with staining largely confined to the cell membrane and cytoplasm. Staining intensity of EGFR was directly correlated with nuclear grade (p=0.000) and TNM stage (p=0.015). PCNA index was significantly higher in EGFR-positive tumors than in EGFR- negative tumors. There was a statistically significant positive correlation between PCNA index and increasing staining intensity of EGFR (p=0.000). In univariate survival analysis, EGFR expression was significantly associated with shortened survival. However, EGFR expression was not an independent prognostic factor by multivariate analysis. These findings suggest that EGFR expression may be an important cause of tumor cell proliferation in renal cell carcinoma and further studies are needed to evaluate whether EGFR expression analysis provides independent prognostic information.

Expression of bcl-2 and p53 Protein in Premalignant Lesion and Invasive Squamous Cell Carcinoma of the Uterine Cervix.: Hyun Chang Joo, Kwan Kyu Park, Sang Sook Lee, Eun Sook Chang, Tae Sung Lee, Soon Do Cha, Young Jae Lee; Korean J Pathol. 2000;34(4):280-287.

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Abstract PDF: In order to understand the possible involvement of bcl-2 and p53 proteins in the tumorigenesis of the cervical cancer and precancerous lesion, we studied the expression patterns of bcl-2 and p53 proteins in 25 cases of carcinoma in situ, 12 cases of microinvasive cervical carcinoma, and 37 cases of invasive cervical carcinoma, respectively. By immunohistochemistry, 76% of in situ carcinoma, 83.3% of microinvasive cervical carcinoma, and 60.9% of invasive cervical carcinoma were positive for bcl-2, while the staining of basal cell layers, columnar cells, and squamous metaplastic epithelium of normal cervical epithelium were positive for bcl-2 in 91.9%, 73.1%, and 81.8% of cases, respectively. Furthermore, two out of fourteen cases of invasive cervical carcinoma with lymph node metastasis were positive for bcl-2. p53 was expressed in 72.7% of condyloma or dysplasia, 12% of in situ carcinomas, 33.3% of microinvasive cervical carcinoma, and 43.5% of invasive cervical carcinomas without metastasis. Six out of fourteen cases of invasive cervical carcinoma with lymph node metastasis were positive for p53 immunostaining. In contrast, 5.4% of basal cells and 9.1% of squamous epithelium, and none of the columnar cells in normal cervical epithelium were positive for p53. In summary, the bcl-2 protein was highly expressed in the proliferative lesion of reserve cells, such as normal reserve cells, columnar cells, squamous metaplasia, carcinoma in situ, and microinvasive squamous cell carcinoma. p53 expression was increased in condyloma, carcinoma in situ, and invasive carcinoma where the reserve cells were non-proliferative. Based on these findings, we propose that bcl-2 and p53 protein are involved in the development and progression of uterine cervical carcinoma.

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.

Cytoskeletal Changes in Cortical Dysplasia.: Min Young Lee, Jae Hun Chung, Young Jong Woo, Hyoung Ihl Kim, Min Cheol Lee; Korean J Pathol. 2000;34(4):300-309.

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Abstract PDF: Cortical dysplasia is a cause of intractable epilepsy and a candidate for surgical resection to control epileptic attacks. The neuronal cytomegaly and balloon cell change are the diagnostic hallmarks of cortical dysplasia. Little research has been performed about the normal-sized dysplastic neuron which has complex arborizing dendrites and lacks in its polarity. The aim of this study was to define the histopathologic characteristics of the neurons in cortical dysplasia. Twelve cases of cortical dysplasia who underwent partial lobectomy for intractable seizures were selected and immunohistochemical staining for NF-M/H, MAP2, tau, and ubiquitin was performed. The perikarya and dendrite of dysplastic neurons were more intensely labeled with antibodies for the high and medium molecular weight neurofilament proteins (NF-M/H) than normal neurons. Immunoreactivity with the MAP2 antibody expressed mainly within the somatodendritic regions was present in the dysplastic or normal neurons without any significant difference in intensity. The complex arborizing dendrites of dysplastic neurons were easily identified due to pronounced immunoreactivity within the somatodendritic regions. Immunoreactivity with the primary antibody against tau and ubiquitin was present in the normal-looking neurons as well as the dysplastic neurons. This study suggests that the dysplastic neurons in cortical dysplasia are accompanied by changes of cytoskeletal neurofilaments, and the immunohistochemical stains for NF-M/H, MAP2, tau, and ubiquigin are useful to detect them.

Case Reports

Multicystic Renal Dysplasia with Ipsilateral Ectopic Ureteral Orifice and Seminal Vesicle Cyst: A case report.: Hyun Jin Son, Joo Heon Kim, Myoung Jae Kang; Korean J Pathol. 2000;34(4):310-313.

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Abstract PDF: Renal dysplasia results from aberrant metanephric histogenesis caused fundamentally by a defect in inducer tissue or responding tissue. Dysplastic kidneys vary tremendously in gross and microscopic appearance but are characterized by abnormal organization and a mixed population of primitive structures, such as fetal or immature cartilage, dysplastic ducts, immature tubules, and undifferentiated mesenchyme. We report a case of unilateral multicystic renal dysplasia associated with an ipsilateral ectopic ureteral orifice entering a seminal vesicle cyst in a 33-year-old man. He was admitted due to primary infertility which had developed three years ago. The his semen analysis revealed oligospermia. No evidence of a family history of renal dysplasia was reported. Microscopic examination showed that the entire kidney was composed of cysts lined by flattened cells, dysplastic ducts and immature tubules surrounded by collars of spindle cells, primitive mesenchyme, and a few aberrantly formed glomeruli.

Pseudosarcomatous Metaplastic Carcinoma of the Breast with Extensive Cystic Change: A case report.: Ji Shin Lee, Jong Jae Jung, Dong Sug Kim; Korean J Pathol. 2000;34(4):314-317.

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Abstract PDF: Metaplastic carcinomas (carcinomas with metaplasia) of the breast are difficult to accurately diagnose and classify because of their rarity and varied histologic patterns. Cystic change can be encountered in mammary carcinoma, especially in carcinoma with squamous metaplasia, but are rare in pseudosarcomatous metaplastic carcinoma. We recently experienced a case of pseduosarcomatous metaplastic carcinoma in a 69-year-old female who had an extensive cystic change in radiologic and histopathologic findings. The precise cell type that gives rise to metaplastic carcinomas remains uncertain. Immunohistochemical findings raised the possibility of the myoepithelial nature of the tumor.

Hyalinizing Trabecular Carcinoma of the Thyroid Gland: A report of two cases.: Kyu Yun Jang, Joo Heon Kim, Myoung Ja Chung, Woo Sung Moon, Myoung Jae Kang; Korean J Pathol. 2000;34(4):318-322.

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Abstract PDF: We report two cases of hyalinizing trabecular carcinoma (HTC) of the thyroid gland. These two patients were euthyroid women aged 36 and 65 years of age. The tumors were encapsulated and measured 0.8 and 4.0 cm in diameter, respectively. Histologically, the tumors were composed of a compact proliferation of cells in a lobular and trabecular pattern with an intervening hyalinized, fibrotic vascular stroma. Occasionally the cells were arrayed in microfollicles. Multiple and serial sections showed cords of tumor cells invading into the capsule in both cases and vascular invasion in one case. These findings suggested that HTCs are a malignant counterpart of hyalinizing trabecular adenoma, similar to conventional follicular tumor. Positive immunostaining of tumor cells for thyroglobulin and negative staining for high molecular weight cytokeratin, cytokeratin 19, neuron specific enolase, chromogranin, and synaptophysin allowed distinction from medullary carcinoma. Even though HTCs are an heterogeneous group of tumors, the present two cases are probably variants of follicular carcinoma rather than papillary carcinoma.

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