Journal of Pathology and Translational Medicine

Volume 36(4); August 2002

Original Articles

Tissue Array Method for Large Scale Clinicopathologic Study.: Woo Ho Kim; Korean J Pathol. 2002;36(4):199-204.

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Abstract PDF: Tissue array consists of a slide containing hundreds or thousands of cases, making this method useful for rapid analysis of molecular markers in a large number of cases. The method significantly facilitates and accelerates the clinicopathologic analysis of cancer. To maximize the efficacy of the tissue array method in pathologic study, the pros and cons of this method should be understood. In this review, the history and a detailed method of tissue array production is described, emphasizing the advantage of the large core size (2.0 mm). Some methological points, including slide storage, microtoming, core size, reliability, and data analysis, are discussed.

Clonality Study in Carcinosarcomas and Malignant Mixed Epithelial Tumors.: Eun Jung Park, Yoo Duk Choi, Jong Hee Nam, Min Cheol Lee, Chang Soo Park, Sang Woo Juhng, In Seon Choi, Kyung Hee Kim, Chan Choi; Korean J Pathol. 2002;36(4):205-211.

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Abstract PDF: BACKGROUND
Tumors are usually considered to be clonal progeny of single transformed cells. Carcinosarcomas and malignant mixed epithelial tumors are examples where controversies exist regarding the singularity or multiplicity of their cell of origin.
METHODS
The authors examined the clonality of carcinosarcomas (7 cases) and malignant mixed epithelial tumor (5 cases) in female patients by X-chromosome inactivation as a marker. Each component of the tumors were picked up by the laser capture microscope. The polymorphic exon 1 CAG trinucleotide repeat in the X-linked human androgen receptor (HUMARA) gene was amplified by a polymerase chain reaction before and after treatment of the methylation-sensitive endonuclease HpaII.
RESULTS
Eleven cases were informative for clonality determination. Six out of seven carcinosarcomas and three out of four malignant mixed epithelial tumors revealed the same patterns of X-chromosome inactivation, which suggests that they are monoclonal. In contrast, the patterns of X-chromosome inactivation were different between the two tumor components in each cases of carcinosarcoma and malignant mixed epithelial tumor, indicating that they are of polyclonal origin.
CONCLUSIONS
These observations show that although most of carcinosarcomas and malignant mixed epithelial tumors are of monoclonal origin, some of them are of polyclonal origin. This finding suggests that these tumors are genuinely polyclonal, and that they originated in the neoplastic transformation of more than one somatic cells

Prenatal Development of Human Lip with Immunohistochemical Study.: Su Jung Hong, Young Joon Lee, Yeon Sook Kim, Suk Keun Lee, Je G Chi; Korean J Pathol. 2002;36(4):212-221.

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Abstract PDF: BACKGROUND
This study is aimed to elucidate the developmental pattern of human fetal lip by histological and immunohistochemical examinations.
METHODS
Totally 231 normal human lip tissues obtained from autopsied fetuses were fixed with 10% buffered formalin, sectioned in cross and longitudinal directions, routinely stained for H&E and performed for immunohistochemistry with antibodies of S-100 protein, proliferating cell nuclear antigen (PCNA), transglutaminase C (TGase-C), metalloproteinase (MMP)-3, MMP-10, tenascin, KL1, K8.12, E-cadherin, tissue inhibitors of matrix metalloproteinase (TIMP)-1, TIMP-2 and total keratin (TK).
RESULTS
The lip structure first appeared as an orifice of stomodeum around the 7-8th week of gestation, and a major structure of the midface was observed by the 11-12th week. As the squamous epithelium of the lip became thick and was keratinized, the vermilion border became distinguished in the 15-16th week, and the lip structure was almost completed with the presence of orbicularis oris muscle in the lingual side of vermilion border by the 17-18th week. Immunohistochemically, the vermilion border showed strong reactions for tenascin, E-cadherin and MMP-3 and increased positivity for PCNA, cytokeratins (TK, KL1, K8.12), and TGase-C.
CONCLUSIONS
With the above findings we suppose that the cytodifferentiation of vermilion border epithelium plays an important role for the development of human fetal lip.

Expression of p53, p21waf1/cip1, Cyclin D1 and Rb in Gastric Epithelial Proliferative Lesions.: Hyoung Joong Kim, Tae Jin Lee, Eon Sub Park, Jae Hyung Yoo; Korean J Pathol. 2002;36(4):222-231.

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Abstract PDF: BACKGROUND
Aberrations of cell cycle-related genes have been reported to contribute to the formation and development of various human tumors. To investigate the gastric carcinogenesis, the expression of cell cycle-related genes (p53, p21wafl/cipl, cyclin D1 and Rb protein) compared to the morphological changes of gastric epithelial lesions were studied.
METHODS
The expression of p53, p21wafl/cipl, cyclin D1 and Rb protein was immunohistochemically studied in a series of surgical specimens including the 36 normal/regenerating lesions and the 127 gastric epithelial proliferative lesions (GEPLs). The gastric epithelial proliferative lesions consisted of 25 regenerating epithelia with atypias (REAs), 27 low grade gastric dysplasias (LGDs), 17 high grade dysplasias (HGDs), 24 early gastrc carcinomas (EGCs), and 34 advanced gastric carcinomas (AGCs).
RESULTS
The frequency of p53 protein overexpression was significantly associated with histologic grades of GEPLs (p=0.031); occurring in 4% of REAs, in 14.8% of LGDs, in 23.5% of HGDs, in 41.7% of EGCs and 58.9% of AGCs. The p21 wafl/cipl immunohistochemical reaction showed superficial eccentric positivity, representing an inverse correlation with histologic grades of GEPLs (p=0.04); occurring in 83.4% of normal/regenerating lesions, in 80% of REAs, in 74.1% of LGDs, in 29.4% of HGDs, 20.8% of EGCs and 8.8% of AGCs. Although Cyclin D1 and Rb proteins were expressed highly in the GEPLs, the frequency of both proteins were insignificantly associated with histologic grades of GEPLs (p=0.092). However, cases with both the Rb and cyclin D1 positivity were increased with statistical significance along histologic grades of GEPLs (p=0.044).
CONCLUSIONS
The altered expression of p53, p21, Rb, and cyclin D1 was considered to be related to dysplastic progression and advancement of malignancy in GEPLs. Therefore, immunohistochemical studies of cell cycle related proteins and a combined analysis may be useful for estimating and following up cases of GEPLs.

Expression of Proliferating Cell Nuclear Antigen (PCNA) of Major Intrahepatic Bile Duct Epithelium in Resected Liver Tissue with Hepatolithiasis and Hepatolithiasis Associated with Cholangiocarcinoma.: Shi Nae Lee, Sun Hee Sung, Woon Sup Han; Korean J Pathol. 2002;36(4):232-237.

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Abstract PDF: BACKGROUND
Histologic progressive changes of bile duct epithelium with hyperplasia, dysplasia and cholangiocarcinoma could be caused by hepatolithiasis. To be clarified as a neoplastic process, this histologic process should be evaluated with various aspects of cell biology.
METHODS
Immunohistochemical study of proliferating cell nuclear antigen (PCNA) was performed on 45 cases (10; normal, 15; hyperplasia, 14; low-grade dysplasia:LGD, 6; high-grade dysplasia: HGD) of hepatolithiasis and 10 cases (all HGD) of hepatolithiasis with cholangiocarcinoma.
RESULTS
In the hepatolithiasis, mean PCNA labelling indices (LI) of normal, hyperplasia, LGD and HGD of major intrahepatic bile duct epithelium were 24.5+/-4.3, 51.5+/-0.1, 62.0+/-.4 and 84.7+/-.3, respectively and gradually increased. Mean LI of PCNA in HGD of major intrahepatic bile duct epithelium of hepatolithiasis with cholangiocarcinoma was 68.7+/-.7, which was similar to that of LGD in hepatolithiasis without cholangiocarcinoma.
CONCLUSIONS
Histologic transformation through hyperplasia, dysplasia and carcinoma in major intrahepatic bile duct epithelium of hepatolithiasis may be a neoplastic process if these histologic changes are evaluated in the cellular proliferation aspect.

The Effect of Ischemic Preconditioning in Rat Liver: The Expression of Interleukin-1 and Nuclear Factor-B.: Kum Yoon Seup, Soo Kyoung Lee, Sun zoo Kim, Eun Kyoung Kwak, Ji Young Park, Tae In Park, Han Ik Bae, Yoon Kyung Sohn, In Soo Suh; Korean J Pathol. 2002;36(4):238-242.

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Abstract PDF: BACKGROUND
A short period of ischemia and reperfusion, called ischemic preconditioning, protects various tissues against subsequent sustained ischemic insult. Apoptosis of hepatocytes and sinusoidal endothelial cells are a critical mechanisms of injury in the ischemic liver. Because nuclear factor-B (NF-B) has a significant role in the cell survival, we hypothesized that ischemic preconditioning protects by inhibition of apoptosis through the expression of NF-B, induced by interleukin-1 (IL-1), which is known for enhancement of its transcription and activation.
METHODS
We induced ischemia and reperfusion on rat liver, and performed in situ terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labelling assay and polymerase chain reaction for IL-1 mRNA and NF-B mRNA.
RESULTS
Apoptosis of hepatocytes and sinusoidal endothelial cells, assessed by in situ TUNEL assay, was significantly reduced with preconditioning. The expression of IL-1 mRNA and NF-B mRNA are seen on discrete monoclonal bands around 344 and 356 base pairs, in comparison with normal rat liver, but, there was no significant difference between the ischemia-reperfusion group and the preconditioning group.
CONCLUSIONS
We suggest that ischemic preconditioning confers dramatic protection against prolonged ischemia via inhibition of apotosis through the expression of IL-1 inducing NF-B and its activation. However, we need further study in the activity of NF-B, such as nucleotide shift assay, because the activity of NF-B is regulated by binding of the inhibitory protein, IB.

Comparing Fluorescence In Situ Hybridization and Immunohistochemistry to Determine the HER-2/neu Status in Breast Carcinoma.: Kyeongmee Park, Jungyoen Kim, Sungjig Lim; Korean J Pathol. 2002;36(4):243-248.

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Abstract PDF: BACKGROUND
Identification of HER-2/neu status is important in predicting the response to specific chemotherapy in breast carcinoma patients and HER-2/neu status is associated with poor clinical outcome even with systemic chemotherapy. Introduction of fluorescence in situ hybridization (FISH) allows an accurate assessment of the level of gene amplification with information about distribution of gene copies in histologic sections.
METHODS
HER-2/neu status was performed on paraffin sections of 176 primary breast carcinomas by FISH, using PathVysion and by immunohistochemistry (IHC), using HercepTest. The results of HER-2/neu amplification was compared with clinical and pathological prognostic factors.
RESULTS
HER-2/neu amplification and overexpression were detected in 51 tumors (29.0%) by FISH and 32 tumors (18.2%) by IHC. The results of each method agreed with each other in 157 tumors (concordance: 89.2%, kappa=0.783). HER-2/neu amplification was associated with poor nuclear grade, marked nuclear pleomorphism, and presence of the combined ductal carcinoma in situ in the invasive ductal carcinomas as well as Van Nuys grade of the ductal carcinoma in situ component (p<0.05).
CONCLUSIONS
The comparison of FISH and IHC demonstrated an excellent correlation of HER-2/neu overexpression 2+ and 3+ with gene amplification. However, FISH may be a more accurate and reliable method for negative and 1+ cases. HER-2/neu amplification proves to be of prognostic relevance.

Expression of Inducible Nitric Oxide Synthase and Nitric Oxide Mediated Apoptosis in Neuronal PC12 Cells after Lipopolysaccharide/Tumor Necrosis Factor-/Interferon- Treatment.: Jiyeon Kim, Jiyoung Kim, Kuseong Kang, Eunkyoung Kwak, Jiyoung Park, Taein Park, Yoonkyung Sohn; Korean J Pathol. 2002;36(4):249-256.

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Abstract PDF: BACKGROUND
Inducible nitric oxide synthase (iNOS) has been detected in a number of pathologic conditions in the central nervous system. This study was investigated the patterns of iNOS expression in the neuronal PC12 cell and the effects of nitric oxide on the apoptosis of PC12 cells.
METHODS
The stimulating agents for induction of iNOS expression in PC12 cells were bacterial lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-), and interferon-gamma (IFN-).
RESULTS
The expression iNOS mRNA and protein in PC12 cells stimulated with LPS/TNF-/IFN- were profoundly increased. The expression of iNOS mRNA arose at 6 hours, peaked at 12 hours, and declined to 48 hours after LPS/TNF-/ IFN- treatment. iNOS protein was increased up to 24 hours in LPS/TNF-/IFN- treated PC12 cells while the expression of nNOS was unaffected. Accumulation of NO derivatives in the culture media was markedly increased at least at up to 48 hours after LPS/TNF-/IFN- treatment. The induction of iNOS expression and NO production in differentiated PC12 cells was correlated with apoptotic cell death judged by transmission electron microscopy and DNA fragmentation from the results of the Terminal deoxynucleotidyl-transferase-mediated dUDP biotin nick end-labeling (TUNEL) method. After treatment with NOS inhibitor, N-monomethylarginine (NMMA), a profound decrease in NO production by LPS/TNF-/IFN- treated PC12 cells was noted. And the LPS/TNF-/IFN- induced apoptosis was prevented by the NMMA treatment.
CONCLUSIONS
From the above results it is concluded that the expression of iNOS in differentiated PC12 cells is induced by the combined application of LPS, TNF-, and IFN-. And the apoptosis of cultured PC12 cells is mediated by iNOS-derived NO.

Case Reports

Uterine Leiomyomas with Perinodular Hydropic Degeneration: A Report of Two Cases.: Sung Nam Kim, Jaejung Jang, Kyu Rae Kim; Korean J Pathol. 2002;36(4):257-261.

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Abstract PDF: Hydropic degeneration is a frequent degenerative change in otherwise typical uterine leiomyomas. Very rarely, however, a significant amount of edema fluid accumulates around the fascicles of neoplastic smooth muscle bundles and forms the characteristic multinodular growth pattern that is called perinodular hydropic degeneration of leiomyoma (PHDL). The gross findings, showing a vague worm-like appearance and very rarely having an extrauterine extension, and the microscopic features, showing perinodular retraction artifacts forming pseudovascular spaces, make it difficult to differentiate the tumor from intravenous leiomyomatosis or myxoid leiomyosarcoma. We described two cases of leiomyomas showing perinodular hydropic degeneration (PHD), a condition that has rarely been described in English literature, and discussed the mechanism of forming "extrauterine extension" or cotyledonoid features. One of our cases showed the typical features of cotyledonoid dissecting leiomyoma, the other showed those of intramural dissecting leiomyoma. An awareness of the gross and microscopic findings of PHDL is important not to overdiagnose a benign smooth muscle neoplasm as a more aggressive type of tumor. It is thought that intramural dissecting leiomyoma, cotyledonoid dissecting leiomyoma, and PHDL are not distinct, but closely related subtypes showing different phases of evolutionary changes.

Uterine Low Grade Endometrial Stromal Sarcoma Presented as Extrauterine Masses: A Case Report.: Sun Young Jun, Hongil Ha, In Ae Park, Kyu Rae Kim; Korean J Pathol. 2002;36(4):262-265.

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Abstract PDF: Endometrial stromal sarcoma (ESS) is a mesenchymal neoplasm that usually occurs as a primary tumor of the uterine corpus, but rarely arises in other sites, such as the ovary, the pelvic cavity, mesentery, omentum, and serosal or intramural portions of the large intestine. We present a case in which multiple nodules of ESS involving the taenia coli of the ascending colon were accompanied by grossly and radiologically unrecognized small, endometrial stromal lesions (less than 0.5 cm in the greatest dimension) with only focal marginal irregularities in the subsequent hysterectomy specimen. Whether this small sized endometrial stromal tumor is an incidentally associated endometrial stromal nodule (ESN) or a small sized, low grade ESS that was preceded by metastatic lesion is debatable. However, endometrial stromal tumors with tongue-like protrusions and associated fibroblastic stromal reaction around the tumor strongly favored these nodules being the small uterine ESS mimicking ESN. We propose that meticulous search for the detection of uterine ESS is mandatory before making a diagnosis of primary extrauterine ESS even in cases having a grossly or radiologically normal uterus and that the extent of focal irregularities of ESN should be more clearly defined for the correct diagnosis of ESS and ESN.

Fatal Strongyloidiasis with Residual Cutaneous Larvae: An Autopsy Case Report.: Na Rae Kim, Dae Su Kim, Joungho Han, Dong Cheol Choe; Korean J Pathol. 2002;36(4):266-270.

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Abstract PDF: Strongyloides stercoralis hyperinfection in immunocompromised patients is difficult to control due to delayed diagnosis, especially in nonendemic areas. A 70-year-old diabetic woman came in with an intermittent diarrhea. She received massive steroid therapy for a week under the impression of idiopathic gastrointestinal eosinophilic syndrome. Diagnosis of strongyloidiasis was made by demonstration of filariform larvae in two repeated sputum specimens two months later. Despite massive administration of albendazole, she died of diabetic ketoacidosis and septic shock. Autopsy revealed a diffusely thickened bowel wall, superimposed invasive pulmonary aspergillosis and the near total destruction of the lungs. Filariform larvae were detected only in the cutaneous lesions. It was presumed that Strongyloides stercoralis hyperinfection was caused by autoinfection in the patient's immunosuppressed status. The present case has two clinical importances; first, intensive treatment with albendazole could erradicate parasites except for the skin but sepsis presumably occurred due to a hypersensitivity reaction against liberated endotoxins during the death of the parasites by the drug. Second, cutaneous parasitic lesion resists the intensive antihelminthic treatment in an immunocompromised host.

Intestinal Metastasis of Osteosarcoma Presenting with Intussusception: A Case Report.: Seong Ho Yoo, Min A Kim, Kyu Joo Park, Joon Koo Han, Sang Hoon Lee, Chong Jai Kim, Eui Keun Ham; Korean J Pathol. 2002;36(4):271-273.

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Abstract PDF: Metastatic osteosarcoma most commonly affects the lungs and other bones. Intestinal intussusception caused by metastatic osteosarcoma is very rare. We report a case of metastatic osteosarcoma of the intestine in a 39-year-old female. She underwent surgical resection of the left femur due to osteosarcoma and received additional chemotherapy 3 years ago. Pulmonary metastasis was found two years later and the patient complained of abdominal pain, nausea and vomiting after 8 months following excision of the lung nodules. Abdominal computed tomography revealed intussusception with a suspected polypoid mass in the distal portion of the jejunum. The histologic findings of the resected bowel were those of osteosarcoma. This is the first case of documented intestinal metastasis of osteosarcoma in Korea. It is suggested that the tumor metastasis to the small intestine should be considered in patients with previous osteosarcoma, when the patient presents with acute abdominal symptoms and intussusception.

Primary Intrasellar Schwannoma: A Case Report.: Na Rae Kim, Yeon Lim Suh; Korean J Pathol. 2002;36(4):274-277.

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Abstract PDF: Primary intrasellar schwannomas or neurilemmomas occur rarely and mimic pituitary adenoma, radiologically and clinically. The authors describe the 6th case of primary intrasellar schwannoma mimicking a nonfunctioning pituitary macroadenoma, clinically as well as radiologically. Light microscopically, the present case did not show the typical histology of conventional schwannoma and the confirmative diagnosis was made with the aid of immunohistochemistry and electron microscope. Here, we review the possible hypotheses for pathogenesis of sellar schwannomas on unusual locations.

Idiopathic Hypertrophic Spinal Pachymeningitis: A Case Report.: Eun Kyung Kim, Wan Seop Kim, Jong Eun Joo, Won Mi Lee, Byng Kwan Moon, Hyun Sook Kim; Korean J Pathol. 2002;36(4):278-280.

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Abstract PDF: We report a case of idiopathic hypertrophic spinal pachymeningitis in a 56-year-old woman who complained of a tingling sensation and progressive weakenss of both legs since 6 months prior, and then was unable to walk for 1 week. Magnetic resonance imaging showed a low signal intensity of dural and epidural mass in the T7-T11. The mass was concentrically compressing the spinal cord and extending to the paraspinal area through the intervertebral foramina. Total laminectomy from T7 to T12 and mass removal were done. The mass was composed of markedly thickened dura mater. Microscopic examination showed fibrous thickening with hyalinization and infiltration of chronic inflammatory cells, mainly lymphocytes. Idiopathic hypertrophic spinal pachymeningitis is a rare disease causing progressive paraparesis that can resemble other disorders associated with spinal compression.

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