Journal of Pathology and Translational Medicine

Volume 32(4); April 1998

Original Articles

The Role of gadd and p53 Genes in Apoptosis and Cell Cycle Delay by Genotoxic Agents.: Jung Young Lee, Jung Duk Lee, Seung Myung Dong, Eun Young Na, Min Sun Shin, Su Young Kim, Sug Hyung Lee, Won Sang Park, Nam Jin Yoo; Korean J Pathol. 1998;32(4):239-247.

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Abstract PDF: The aim of this study was to investigate the relationships between the gadd genes expression and an apoptosis induction in two different growing cell types after treatments with cisplatin and methylmethan sulfonate (MMS). We have examined the kinetics and specificity of gadd45 and gadd153 expression following cisplatin and MMS treatments to HL-60 cells and primary cultured human kidney (HKN) cells. We have also determined an induction time of apoptosis by DNA fragmentation analysis and the presence of the cell cycle arrest by a flow cytometric measurement. The results were as follows. In non-adherent HL-60 cells, a typical ladder pattern was observed within 4 hours after treatments of 20 micrometer of cisplatin and 100 microgram/ml of MMS. At the same time while adherent HKN cells failed to exhibit a ladder pattern at even higher doses of genotoxic agents. Since HL-60 cells do not have p53 gene, these findings suggest the presence of a p53-independent apoptotic pathway. The increasing patterns of the mRNA levels of gadd45 and gadd153 varied with the type of genotoxic agents. In the case of MMS treatment, the induction was rapid and transient, regardless of the cell types. The mRNA level peaked at 4 hours after MMS treatment and markedly decreased after 12 hours. On the other hand, cisplatin-induced transcriptions of gadd45 and gadd153 continued to increase for at least 24 hours and reached a peak level at 48 hours after cisplatin treatment, regardless of the cell types. HL-60 cells revealed G2 arrest following 24 hours after cisplatin and MMS treatments. These findings suggest that the regulation mechanism of apoptosis between adherent and non-adherent cells, might be different and that gadd45 and gadd153 might have an important role in DNA repair rather than apoptosis. Also, the findings suggest that an expression pattern of gadd45 and gadd153 might be different according to the type of genotoxic agents.

Expression of bcl-2 Protein in Gastric Adenoma and Adenocarcinoma.: Young Sill Kim, Byung Kee Kim, Sang In Shim; Korean J Pathol. 1998;32(4):248-254.

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Abstract PDF: The bcl-2 oncoprotein confers a survival advantage to cells by blocking programmed cell death. Overexpression of bcl-2 probably plays a role in tumorigenesis, and the expression of the bcl-2 protein has been investigated in many kinds of tumors. However, there have been only a few reports on expression of bcl-2 in human gastric adenocarcinoma. The aim of this study was to investigate the relationship between the expression of bcl-2 protein and several clinical and pathological parameters such as age, tumor site, size, histological type, depth of invasion, Lauren's classification, and grade. Immunohistochemical staining using monoclonal bcl-2 protein antibody, clone 124, was performed on paraffin embedded specimens from 23 gastric adenomas and from 45 gastric adenocarcinomas. The results are as follows. 1. Variable intensity of epithelial staining was noted from case to case, although the lymphocytic component showed similar intensity in all examples. The staining was located at the gland and mucous neck region of non-neoplastic epithelium. 2. The more differentiated type of gastric adenocarcinoma showed the higher expression rate and intensity. 3. The relationship between the expression rates of bcl-2 protein and tumor grade (adenoma early gastric adenocarcinoma advanced gastric adenocarcinoma) was statistically significant. The reactivity in adenoma was somewhat stronger with a uniform pattern, while in adenocarcinoma it was much weaker with a heterogenous pattern. 4. Intestinal type carcinomas by Lauren's criteria showed a higher expression rate and intensity than diffuse type. These results suggest that the bcl-2 expression would be found in the early phase of gastric tumorigenesis, and the expression rate and intensity would decrease according to the tumor progression.

Expression of p53 and MDM2 Proteins in Thyroid Carcinomas.: Chang Hun Lee; Korean J Pathol. 1998;32(4):255-260.

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Abstract PDF: The nuclear protein p53 is a tumor suppressor gene product that functions in pathways of cell cycle control and in the repair of damaged DNA. The MDM2 gene codes for a cellular protein that can complex the p53 gene product and negatively regulate its function. Interestingly an autoregulatory feedback loop is set up to regulate the activity of p53 protein and MDM2 gene expression. To evaluate the role of p53 and MDM2 proteins in thyroid carcinogenesis, the author tried immunohistochemical studies in the paraffin embedded sections of 58 thyroid carcinoma cases, including 30 papillary carcinomas, 20 follicular carcinomas, and 8 undifferentiated carcinomas. p53 protein expression was found in 8 cases (26.7%) of papillary carcinomas. It was found in all the cases of undifferentiated carcinomas and not found in the follicular carcinomas. The staining intensity and the frequency scores were more prominent in undifferentiated carcinomas. MDM2 protein expression was found in only 6 cases of papillary carcinomas. It was not expressed in follicular carcinomas or undifferentiated carcinomas. The staining intensity is less than moderate and the frequency score was usually focal. In papillary carcinomas, the correlation of p53 and MDM2 expression was insignificant. In conclusion, p53 may play a major role in tumorigenesis or the progression of undifferentiated carcinomas, but not in the other carcinomas. As compared with papillary carcinomas, follicular carcinomas are regarded as taking a different carcinogenetic pathway. The overexpression of p53 and MDM2 proteins in papillary carcinomas is presumed not to be necessarily correlated with the p53-MDM2 complex formation.

Expression of TGF-beta1 Protein in Macrophages of Tuberculous Granulomas.: Jong Im Lee, Jung Ran Kim, Tae Jung Jang, Dong Hoon Kim; Korean J Pathol. 1998;32(4):261-265.

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Abstract PDF: TGF-beta1 expression was studied in 25 patients with tuberculosis (lung, 9 cases and lymph node, 16 cases) using a polyclonal antibody in formalin-fixed paraffin embedded tissue. Nineteen cases (76.0%) out of 25 cases showed TGF-beta1 expression. TGF-beta1 was present in cytoplasm of epithelioid cells and Langhans' giant cells. Pulmonary tuberculosis and tuberculous lymphadenitis showed different patterns of staining. Five of 9 cases of pulmonary tuberculosis were positive for TGF-beta1: four of acid-fast bacilli positive cases (4/5, 80.0%) and one of acid-fast bacilli negative cases (1/4, 25.0%). However, high expression of TGF-beta1 was detected in tuberculous lymphadenitis of both acid-fast bacilli positive group (3/4, 75.0%) and acid-fast bacilli negative group (11/12, 91.7%). TGF-beta1 was also expressed in all of 6 cases of BCG-induced tuberculous lymphadenitis: 2 acid-fast bacilli positive and 4 acid-fast bacilli negative cases. TGF-beta1 expression was shown in 19 cases (86.4%) of 22 in active tuberculosis, while no TGF-beta1 expression was detected in any cases of inactive, healed tuberculosis (p<0.008). This study supports that the TGF-beta1 expression of epithelioid cells may alter their function resulting in the impaired antimycobacterial activity. Thus the increased production of TGF-beta1 may be one of the important mechanisms by which Mycobacterium tuberculosis avoids destruction by host macrophages.

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.

Prenatal Development of Sebaceous Gland: Morphologic and Morphometric Observation.: Im Joong Yoon, Je Geun Chi, Kye Yong Song; Korean J Pathol. 1998;32(4):273-282.

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Abstract PDF: This study was conducted to illustrate the histological and morphometric features of the sebaceous gland of human fetal skin. For this purpose, we studied 12 human embryos and 60 fetuses from the 4 th to 38 th week of gestation. In each case, we sampled eight different areas of skin, i.e., scalp, forehead, face, chest, abdomen, back, extremity, and palm and sole. Through routine tissue processing, hematoxylin and eosin preparations were made for morphology and morphometric analysis. The sebaceous gland anlagen is noted in the face and scalp by the 14th week of gestation, being subsequently generalized in other parts of the body, namely by 16th week of gestation. The lobation of the sebaceous gland subsequently differentiated into multilobular appearance in the face and scalp by the 17th week of gestation and in the chest and abdomen by the 26th week of gestation. The sebaceous ducts were seen by the 21th week of gestation in face and scalp, and in the chest and abdomen by the 27th week of gestation. In morphometric observation, the number and diameter of sebaceous gland were reached its peak during the 21st to 24th week of gestation, and then decreased gradually until it became constant in later days of the gestational period. In general, cephalic portion of the body had more sebaceous glands and also was larger in diameter. This difference became negligible as fetuses reached the term.

A Study of Correlation between Stage and Angiogenesis f Uterine Cervical Squamous Cell Carcinoma.: Eung Seok Lee, In Sun Kim; Korean J Pathol. 1998;32(4):283-289.

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Abstract PDF: A variety of malignant neoplasms have been shown to induce neovascularization, and in some cases the degree of vascularization appears to correlate with an aggressive behavior and risk of metastasis. We compared the degree of vascularization in 11 benign and 33 cancerous lesions of the cervix. The microvessels were identified by immunohistochemistry using antibody to Factor VIII-related antigen in 44 hystrectomy specimens. Three highly vascularized microscopic fields were selected and counted the number of microvessels in 400 magnification. The proportion of the endothelial cell area was also quantified by using the CAS 200 image analysis system. All 33 cases of carcinomas demonstrated a significantly higher microvessel count and an endothelial cell area than those of the benign lesions (p<0.01). There were no significant difference in microvessel count and endothelial cell area among carcinoma in situ, microinvasive carcinoma and invasive carcinoma (p>0.05). Microvessel count and an endothelial cell area in invasive cancers were not correlated with tumor size, depth of invasion, or histologic type (p>0.05).This study showed cervical cancer induces neovascularization in an early stage but it is difficult to predict prognosis and metastasis with microvessel count and an endothelial cell area.

Expressions of Vascular Endothelial Growth Factor (VEGF), Phospholipase C-gammal and Ki-67 in Squamous Cell Carcinoma and High Grade Squamous Intraepithelial Lesion of Uterine Cervix.: Ki Kwon Kim, Jung Ran Kim; Korean J Pathol. 1998;32(4):290-297.

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Abstract PDF: Angiogenesis is an early event in tumorigenesis and facilitates tumor progression and metastasis. This study was performed to evaluate the expression of vascular endothelial growth factor (VEGF), phospholipase C-gamma1 (PLC-gamma1) and Ki-67, and to assess the relationship between them in cervical squamous cell neoplasia. The materials were fifty cervical squamous cell lesions, consisted of thirty HSIL (6 moderate dysplasia, 11 severe dysplasia, 13 carcinoma in situ), and twenty invasive squamous cell carcinoma (ISCC) cases. Immunohistochemical stain for VEGF, PLC-gamma1 and Ki-67 were done. Expression rate of VEGF was significantly higher in ISCC than in HSIL (p=0.012). PLC-gamma1 expression was significantly higher in ISCC than in HSIL (p=0.004). Ki-67 labelling index was significantly higher in ISCC than in HSIL (p=0.001) and higher in VEGF-positive tumors than in VEGF-negative tumors (p=0.018), but there were no significant differences between PLC-gamma1 expression and Ki-67 labelling index (p>0.05), and between PLC-gamma1 and VEGF (p>0.05). This study suggests that PLC-gamma1 and VEGF may play an important role in tumor cell proliferation and invasion, and these may be a useful marker to predict the possibility of invasion in cervical cancer.

Detection of Minimal Lesion and Identification of Clonality in Malignant Lymphoma.: Young Shin Kim, Chang Suk Kang, Kyun gja Han, Kyo Young Lee, Yong Goo Kim, Won Il Kim, Sang In Shim; Korean J Pathol. 1998;32(4):298-308.

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Abstract PDF: The bone marrow biopsy is an integral part of the staging process in patients with malignant lymphomas. Bone marrow(BM) involvement indicates stage IV disease, but there are always a lot of cases in which clear separation is not possible when based on morphology alone. Additional difficulties are caused by morphologic discordance between the BM and the primary lymphoma. Immunohistochemical stain, mRNA in situ hybridization (ISH) for light chain restriction and polymerase chain reaction (PCR) for IgH CDR3 and TCRgamma were performed to find a minimal lesion and the clonality in formalin fixed paraffin embedded tissues of 39 primary lymphomas and corresponding BM biopsy specimens. As a result, nine morphologically negative bone marrows of 18 lymphomas were positive by PCR (Group I). Among the 6 lymphoma cases with morphologically suspicious BM involvement (Group II), one was confirmed to be positive for marrow involvement by both mRNA ISH and PCR and the other four by PCR alone. The positive bone marrows of Group I and II revealed gene rearrangement at the same site as the primary lesion, suggesting the same clonality. Thirteen of 15 lymphomas with morphologically positive BM (Group III) had the same clonality in the primary lymphomas and the BM lesion. Three cases among the Group III with morphologic discordance also revealed the same clonality by PCR. This study shows that a combination of mRNA ISH and PCR in addition to an immunohistochemical stain improves the diagnostic sensitivity in the detection of BM involvement and identification of clonality. Among the three different methods used, PCR is the most sensitive in detecting a minimal lesion.

Case Reports

Cutaneous Lymphadenoma: A case report and Review of Literature.: Im Joong Yoon, Mee Kyung Kim, Kye Yong Song; Korean J Pathol. 1998;32(4):309-311.

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Abstract PDF: The cutaneous lymphadenoma is a recently described tumor with a distinctive histologic picture representing a basaloid epithelial proliferation and intraepithelial lymphocytic infiltration; it seems to be a benign adnexal neoplasm of uncertain histogenesis. We documented one example of cutaneous lymphadenoma showing typical histologic features. The tumor typically presented as a well circumscribed nodule with scant or no epidermal connections. The proliferating one consisted of multiple rounded lobules of basaloid cells with some degree of peripheral palisading. There was an intense infiltrate of small lymphocytes within the lobules but few in the stroma. No clear adnexal differentiation is noted. Immunohistochemically, the basaloid cells show weak immunoreactivity for high molecular weight keratin and carcinoembryonic antigen, small lymphocytes for T-cell marker and some dendritic cells for S-100 protein. After surgical resection, we found no evidence of local recurrence or distant metastasis for four years, so we considered this tumor as a benign one and diagnosed as cutaneous lymphadenoma by typical histologic features.

Malignant Eccrine Poroma of Abdomen Brief case report.: Jin Ja Park, Young Hee Choi, Kyung Chan Choi, Young Euy Park; Korean J Pathol. 1998;32(4):312-314.

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Abstract PDF: Eccrine porocarcinoma is a rare tumor of the skin. A case report of an eccrine porocarcinoma metastasizing to epidural space of spinal cord and inguinal area with a nine year follow up is described. The patient had a nodular growth of the abdomen with both inguinal lymphadenopathy three years before its first excision. After a follow up of nine years, he complained a weakness of lower extremities and back pain. Extradural mass of 10th thoracic vertebra and left inguinal mass were found. Subsequently, the masses histologically identical to the skin tumor were found.

Adenocarcinoma Arising in Sacrococcygeal Teratoma: A case report.: Hae Jeong Choi, Mi Jin Gu, Yeong Kyung Bae, Joon Hyuk Choi, Jae Hwan Kim; Korean J Pathol. 1998;32(4):315-317.

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Abstract PDF: We experienced a case of adenocarcinoma arising in sacrococcygeal teratoma. The patient was a 52-year-old woman. She was admitted due to one month of sacral pain. She had a sacral mass since birth. On physical examination, anal fistula was present at the perianal area and pus drainage was noted. MR image showed multiple variable-sized cysts with inhomogeneous density. Resected specimen, mesuring 12.5 7.0 cm in diameter, showed multiple variable-sized cystic lesions admixed with grayish solid portion. The cysts contained mucoid material. The microscopic examination showed mature teratoma composed of cysts lined by pseudostratified ciliated columnar epithelium, intestinal mucosa, mature cartilage, bone, and fat tissue. A moderately differentiated adenocarcinoma developed from the cystic area in the mass.

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