Journal of Pathology and Translational Medicine

Volume 36(6); December 2002

Original Articles

Inactivation Pattern of p16 Gene in Non-Hodgkin's Lymphomas.: Hyun Deuk Cho, In Sun Kim; Korean J Pathol. 2002;36(6):365-373.

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Abstract PDF: BACKGROUND
Loss of heterozygosity (LOH) and mutation of the p16 tumor suppressor gene have been detected in non-Hodgkin's lymphomas (NHLs). Recently, hypermethylation of the p16 gene has been reported. The role of p16 gene alterations in the genesis of NHLs and their high-grade transformations require explanation.
METHODS
LOH of D9S171 and IFNA microsatellite markers, DNA hypermethylation, and mutation of exon 1 and 2A were assessed in 43 cases of NHLs. The genetic abnormalities were compared with the protein expression by immunohistochemistry, and they were evaluated according to the histologic subtypes, grades and immunophenotypes.
RESULTS
DNA hypermethylation was the most common p16 gene abnormality and was found in 30 of 39 cases (76.9%). Eight cases (18.6%) showed LOH in one or both microsatellite markers, and five cases (11.6%) showed mutations in exon 1 or 2A. Loss of protein expression was seen in 17 cases (39.5%) and was associated with mutation and LOH. Loss of protein was more frequent in high-grade lymphomas than in low-grade lymphomas.
CONCLUSION
These results suggest that the functional loss of the p16 gene contributes to the development of NHLs, especially to the development of high-grade lymphomas.

Expression of Nitric Oxide Synthase Isotypes in Advanced Gastric Carcinoma.: Kyong Mee Kwon, Young Chae Chu, Tae Sook Hwang; Korean J Pathol. 2002;36(6):374-371.

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Abstract PDF: BACKGROUND
Increased expression of nitric oxide synthase (NOS) isotypes is present in human tumor cell lines and solid tumor tissues. Hypoxia upregulates NOS expression, and nitric oxide (NO) induces mitogenesis among endothelial cells. NO has been known to induce vascular endothelial growth factor (VEGF) expression in carcinoma cells and to induce neovascularization in tumors.
METHODS
The expression and cellular localization of 3 isotypes of NOS was detected by immunohistochemistry in 73 advanced gastric carcinoma tissues along with adjacent normal gastric mucosa; and the relationship to known clinicopathologic parameters, microvascular density, and VEGF expression was analysed.
RESULTS
Forty-four (60.3%), 56 (76.7%), and 52 (71.2%) of the 73 cases revealed eNOS, nNOS, and iNOS expression, respectively. Intestinal type adenocarcinomas tended to have higher activity of eNOS (p=0.000) and nNOS (p=0.001) activities than did the diffuse type adenocarcinomas. All isotypes of NOS (eNOS, p=0.001; nNOS, p=0.005; iNOS, p=0.044) tended to be highly expressed when the tumor was differentiated. There was no significant relationship between any of the 3 NOS isotypes and microvascular density, whereas VEGF was closely related with microvascular density (p=0.000). The expression of VEGF was not related to with any of the NOS isotype expressions.
CONCLUSIONS
From the above results, we speculated that NO may be implicated in the early stage of the gastric carcinogenesis rather than the growth and progression stages, and NO does not appear to affect angiogenesis or VEGF expression in the advanced gastric carcinoma.

Altered Expression of p53, p21WAF1, p16, Rb, Smad4 and c-erbB-2 in Resected Pancreatic Ductal Adenocarcinoma.: Yun Kyung Kang, Woo Ho Kim; Korean J Pathol. 2002;36(6):382-388.

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Abstract PDF: BACKGROUND
Our aim was to undertake a comprehensive analysis of the expression of key molecular markers in a series of pancreatic ductal adenocarcinomas and to determine their association with clinicopathologic variables.
METHODS
By using immunohistochemical staining, we examined the expressions of five tumor suppressor genes (p53, p21WAF1, p16, Rb, Smad4) and a growth factor receptor (c-erbB-2) in 52 surgically resected pancreatic ductal adenocarcinomas.
RESULTS
Abnormal nuclear overexpression of p53 was noted in 28/52 (53.8%) cases. Total loss of p21WAF1, p16, Rb, and Smad4 was detected in 15/52 (28.8%), 33/52 (63.5%), 4/52 (7.7%), and 26/52 (50%) cases, respectively. Overexpression of c-erbB-2 was noted in 21/52 (40.4%) cases. Forty-nine (94.2%) cases revealed aberration of at least one of the markers examined. There was a positive correlation between p53 and c-erbB-2 overexpression (p<0.05). Among the examined genes, overexpression of c-erbB-2 was found to have a positive relationship with the tumor stage (p<0.05). There was also a significant correlation between the histologic grade and the number of abnormally expressed genes per tumor (p<0.05).
CONCLUSION
Among the various tumor-associated proteins evaluated in this study, c-erbB-2 could have the most likely clinical implication.

Stromelysin-3 Expression in Squamous Intraepithelial Lesions and Invasive Squamous Cell Carcinoma of the Uterine Cervix.: Yoo Duk Choi, Eun Jung Park, Jong Hee Nam, Chang Soo Park; Korean J Pathol. 2002;36(6):389-393.

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Abstract PDF: BACKGROUND
Matrix metalloproteinase (MMP) plays an important role in the invasion and metastasis of epithelial neoplasms. Currently, detected stromelysin-3 (ST-3) (MMP-11) is thought to be associated with invasiveness in epithelial neoplasms. However, the study of the expression of stromelysin-3 in the uterine cervix is yet to be delineated.
METHODS
Stromelysin-3 expression in cervical invasive squamous cell carcinoma (SCC) and in squamous intraepithelial lesions (SIL) having potentiality to become invasive was studied by immunohistochemical analysis. We examined the correlation between ST-3 expression and the histopathological parameters of the invasive carcinoma, including growth pattern, lymph node involvement, and degrees of differentiation.
RESULTS
The stromelysin expression rates were as follows; 8.3% in low grade SIL (LSIL), 18.9% in High grade SIL (HSIL), and 75.6% in SCC. A statistical difference in the expression difference was exhibited only between invasive SCC and SIL, but not between LSIL and HSIL, even though HSIL showed a higher expression rate than LSIL. No significant association was found in invasive SCC between ST-3 expression and histopathological parameters.
CONCLUSIONS
ST-3 expression is associated with tumor invasiveness in squamous lesions of the uterine cervix and not with histopathological parameters in invasive SCC.

Alterations of 9p21-22 Region Encoding Genes in Primary Glioblastomas.: Hong Jik Doh, Seong Il Suh, Dong Won Kim, Il Man Kim, Man Bin Yim, Eun Ik Son, Kun Young Kwon, Sang Sook Lee, Sang Pyo Kim; Korean J Pathol. 2002;36(6):394-399.

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Abstract PDF: BACKGROUND
Glioblastomas are one of the most common and aggressive malignant glial tumors occuring in the central nervous system. This study analyzed the status of p15INK4b, p14ARF, p16INK4a, MTAP, IFNA, and IFNB genes in 36 primary glioblastomas to investigate whether the inactivation of these genes participate in primary glioblastoma tumorigenesis.
METHODS
We used polymerase chain reaction, polymerase chain reaction/single strand conformational polymorphism (PCR/SSCP) analysis, and methylation-specific PCR.
RESULTS
Homozygous deletions at the p16INK4a gene were detected in 11 cases (30.5%) of 36 primary glioblastomas, and the promoter hypermethylation was found in 3 cases (8.3%) of 36 primary glioblastomas. In mutational analysis for the p16INK4a gene by PCR/SSCP, there was no abnormal mobility-shifted band in 36 cases of primary glioblastomas. The overall frequency of p16INK4a alterations including homozygous deletion and promoter hypermethylation in 36 primary glioblastomas was 38.8% (14 of 36). Deletions of p15INK4b were noted in 4 cases (11.1%), whereas deletions of the p14ARF and MTAP genes were detected in 1 case of 36 cases of primary glioblastomas. But deletions of the INFA and B genes were not found.
CONCLUSIONS
These results suggest that alterations of the p16INK4a gene can be important mechanisms of the tumorigenesis of primary glioblastomas, and the p16INK4a gene is inactivated by mechanisms including homozygous deletion and promoter hypermethylation.

Expression of Major Gangliosides in Normal and Alzheimer Disease Brain.: Min Cheol Lee, Young Jong Woo, Seung U Kim, Tadashi Tai; Korean J Pathol. 2002;36(6):400-405.

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Abstract PDF: BACKGROUND
GM1 ganglioside-bound amyloid beta-protein (GM1/A) has been reported to be involved with senile plaque formation in Alzheimer disease.
METHODS
To investigate the binding of major gangliosides on senile plaques and neurofibrillary tangles of Alzheimer disease-specific pathology, we developed four monoclonal antibodies -- GM1, GD1a, GD1b, and GT1b -- employing the hydridoma technique, and applied them for immunohistochemical staining at the frontotemporal neocortex and hippocampus of Alzheimer disease brains and age-matched control brains.
RESULTS
Moderate immunopositivity for GM1 and GD1a was noted on the senile plaques and neurofibrillary tangles. Mild immunopositivity for GD1b and GT1b on neurofibrillary tangles was noted. Strong GD1b immunopositivity was observed on a few neurons and neurites. Strong immunopositivity for GT1b, and moderate immunopositivity for GM1 and GD1a were noted on reactive astrocytes.
CONCLUSIONS
These observations suggest that GM1 and GD1a may be involved in the formation of senile plaques as well as neurofibrillary tangles in Alzheimer disease brains.

Lipopolysaccharide/Interferon-gamma Induced Nitric Oxide Production in C6 Glioma Cells: Modulation by Dexamethasone.: Jong Heun Shin, Ku Seong Kang, Ji Yeoun Kim, Sun Zoo Kim, Ji Young Park, Eun Kyoung Kwak, Yoon Kyung Sohn; Korean J Pathol. 2002;36(6):406-411.

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Abstract PDF: BACKGROUND
Glial cell-derived nitric oxide (NO), and its regulation has significant implications for central nervous system pathophysiology. The aim of the present study was to see the production of NO in lipopolysaccharide (LPS)/interferon-gamma (IFN-)-treated C6 glioma cells and the effect of dexamethasone on NO production and apoptosis of LPS/IFN--treated C6 glioma cells.
METHODS
The apoptosis of LPS/IFN- treated C6 glioma cell was examined with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method and the production of NO in culture medium was measured. The expression of iNOS mRNA was examined by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). The effect of the N-monomethyl L-arginine (NMMA) and dexamethasone on the apoptosis and NO production was also examined.
RESULTS
Inducible nitric oxide synthase (iNOS) mRNA and NO production were markedly increased in LPS/IFN--treated C6 glioma cells. The expression of iNOS mRNA arose at 3 hours, peaked at 12 hours, and declined 24 hours after LPS/IFN--treatment. Accumulation of NO derivatives in the culture media was increased at least upto 48 hours after LPS/IFN-. The induction of iNOS expression and NO production in LPS/IFN--treated C6 cells was correlated with apoptotic cell death judged by TUNEL staining. After treatment of NMMA, one of the NOS inhibitors, NO production and apoptosis were markedly decreased. Dexamehasone treatment suppressed the NO production by concentration depenedent manner.
CONCLUSIONS
From the above results it is concluded that the LPS/IFN- induced apoptosis of C6 cells is mediated by iNOS-derived NO and NO production and apoptosis was suppressed by dexamethasone.

Case Reports

Plexogenic Pulmonary Arteriopathy in Congenital Heart Disease: A Report of Two Cases.: Seung Yeon Ha, Kook Yang Park, Hyun Yee Cho, Young Ha Oh, Jae Gul Chung, Dong Hae Chung, Chung Yeul Kim, Han Kyeom Kim; Korean J Pathol. 2002;36(6):412-415.

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Abstract PDF: Hypertensive pulmonary vascular disease can develop in those cases of congenital cardiac shunt in which critical levels of pulmonary artery pressure and flow are reached and exceeded. We have experienced two cases of plexogenic arteriopathy in complex congenital heart disease and tried to evaluate of distribution of arterial lesions by total mapping of the explanted lung. Case 1 and 2 were 12-year-old boy and 36 year-old man. They were treated with combined heart-lung transplantation. Mapping of the both lungs was done, and graded according to Heath and Edward's grading scheme. The elastic pulmonary artery was tortuous, dilated and aortic configuration. Both lungs showed mostly grade 3. Plexiform lesion or veinlike branches of hypertrophied muscular arteries arosed in a lateral branch of a muscular artery that might be proximal to an area of occlusion. Comprising the right and left lung, the right was more severe than the left. By getting closer to the distal part, the grade tended to increase to 4 to 5. By analyzing the pulmonary lobe, severe pulmonary hypertension of grade 4 or 5 was comparatively disseminated throughout the right lung. On the other hand, in the left lung, the grade of the lower lobe was higher than that of the upper lobe, and within the upper lobe, there was a tendency for the grade of inferior segment to be higher than that of the corresponding apical segment.

Splenic Lymphangioma: A Report of Three Cases.: Mi Jung Kim, Kyung Ja Cho, Eun Mi Han, Young Joo Lee; Korean J Pathol. 2002;36(6):416-419.

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Abstract PDF: Splenic lymphangioma is a very rare and benign neoplasm. We report three cases of splenic lymphangiomas found in three women aged 71-years-old, 50-years-old, and 46-years-old. All of the three cases consisted of solitary lesions in the spleen and they were not represented as a part of lymphangiomatosis. Splenectomies were done in all cases and enlarged spleens revealed multicystic masses with variable-sized cysts. Histologically, the cysts were lined by flat endothelial cells and filled with acellular pinkish fluid. The cyst walls mainly consisted of hypocellular fibrous tissue with occasional smooth muscle components. The walls were shared by neighboring cysts, or intervened by interspersed splenic parenchymal components. On immunohistochemical stainings, the lining cells were diffusely positive for CD31 and factor VIII-related antigen (FVIII-RAg), while focally positive for CD34 in all cases.

Primary Sclerosing Cholangitis: A Report of Two Liver Explants.: Sun Young Jun, Jung Sun Kim, Eun Sil Yu; Korean J Pathol. 2002;36(6):420-424.

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Abstract PDF: Primary sclerosing cholangitis (PSC) is usually progressive to the end stage liver disease and a common indication for liver transplantation (LT). We report two cases of liver explants with PSC. Case 1 was that of a 35-year-old male who was admitted for 4 weeks because he had jaundice. He had been treated several times without receiving a definite diagnosis during the last 7 years because he was excreting dark urine. Case 2 was that of a 30-year-old female who had taken a prednisolone for 6 years for treatment of ulcerative colitis. She also had stones and underwent a cholecystectomy and choledocholithotomy 2 years ago. She had complained of epigastric pain and febrile sensation for 2 months. In both cases, serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phospatase, gamma glutamyl transpeptidase, and direct builirubin were elevated. Autoantibodies were not detected. Computerized tomography scan and endoscopic retrograde cholangiopancreatography revealed hepato-splenomegaly, stricture of intra- and extra-hepatic bile ducts, and beaded dilatation of the intrahepatic bile ducts. Despite stent insertions and medication, another episode of jaundice occurred in case 1 and cirrhosis finally developed in case 2. The histopathologic features of liver needle biopsy specimens were nonspecific, while explant livers displayed periductal fibrosis, ductopenia, and/or ductular proliferation, which are characteristic features for PSC.

Mesenchymal Hamartoma of the Liver in Beckwith-Wiedemann Syndrome: A Case Report.: Seong Ho Yoo, Hyo Jin Park, Soo Yoen Cho, Chong Jai Kim; Korean J Pathol. 2002;36(6):425-428.

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Abstract PDF: Beckwith-Wiedemann syndrome is a well-known overgrowth syndrome associated with the presence of a wide variety of anomalies and increased risk of cancers. Less frequently, benign neoplasms also develop. We report a female infant with Beckwith-Wiedemann syndrome who developed a mesenchymal hamartoma of the liver. The patient was born with macroglossia, ear lobe crease, and abdominal distension. Laboratory data showed hypoglycemia, and magnetic resonance image revealed both adrenal enlargement, enhancing mass of the pancreas, and multiple hepatic nodules. The histologic findings of the resected distal pancreas and both adrenals were those of Beckwith-Wiedemann syndrome. Microscopic findings of the liver biopsy specimens were compatible with mesenchymal hamartoma. Hamartoma of the urinary bladder, cardiac fibrous hamartoma, and mixed hamartoma of the liver have been documented previously in association with Beckwith-Wiedemann syndrome. However, to our knowledge, this is the first case report of hepatic mesenchymal hamartoma in Beckwith-Wiedemann syndrome. Because of the paucity of hamartomas in childhood, we should be cautious of other features of Beckwith-Wiedemann syndrome and the present case extends the spectrum of tumor formation in this syndrome.

Ipsilateral Synchronous Renal Cell Carcinoma and Transitional Cell Carcinoma: A Case Report.: Ji Young Park, Eun Kyung Kwak, Tae In Park; Korean J Pathol. 2002;36(6):429-432.

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Abstract PDF: We report a synchronous renal cell carcinoma (RCC) and renal pelvic transitional cell carcinoma (TCC) in the kidney of a 74-year-old man. The kidney was without hydronephrosis. The patient was admitted to the hospital because he had intermittent gross hematuria for three years. Histologically, a section of the specimen revealed a conventional (clear cell) RCC in renal parenchyma just beneath the renal pelvis and a papillary urothelial carcinoma arising from the renal pelvis at the upper pole; the two are completely separated from one another. The tumor cells of the TCC showed an overexpression of c-MET immunohistochemical staining and more intense positive reactivity for p53 immunohistochemical staining than those of the RCC. These findings suggest that c-Met and p53 may be associated with the development of papillary TCC.

Suprasellar Endodermal Sinus Tumor Presenting with Tonic-Clonic Seizure: An Autopsy Case Report.: Min Jin Lee, Hea Soo Koo, Woon Sup Han, Sun Hee Sung, Yong Jae Kim, Hye Young Choi; Korean J Pathol. 2002;36(6):433-439.

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Abstract PDF: We report the clinical course and autopsy findings of a 19-year-old girl with endodermal sinus tumor involving the thalamus, hypothalamus, and basal ganglia. The patient initially had tonic-clonic seizures with abnormal signal involving the right hippocampus, amygdala, basal ganglia, putamen, and dentate gyrus. The signal intensity of the posterior pituitary on T1-weighted images was decreased at the time of admission, which was not associated with clinical symptoms of diabetes insipidus (DI). A huge tumor mass as well as central DI developed within 10 months. The postmortem examination showed gliosis with calcification involving the right basal ganglia, internal capsule, and white matter, in addition to a tumor mass involving the thalamus, hypothalamus, and basal ganglia. Dissemination of tumor cells in the leptomeninges and the gliotic area and hydrocephalus were also noted.

Congenital Desmoplastic Cerebral Glioblastoma: A Case Report.: Hong Il Ha, Seung Mo Hong, Seung Koo Lee, Shin Kwang Khang; Korean J Pathol. 2002;36(6):440-444.

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Abstract PDF: Desmoplastic cerebral glioblastoma has been described recently and is a very rare histologic variant of glioblastoma. We report a case of congenital cerebral glioblastoma associated with intense desmoplastic stromal reaction. A male infant was born at 36 gestational weeks by Cesarian section. He had a brain tumor, which was detected by fetal ultrasonography. The tumor was partially resected 2 months after the day of the boy's birth and totally resected when he was one year old. The microscopic features of the tumor were those of glioblastoma, including high cellularity, frequent mitotic figures, vascular endothelial proliferation, and geographic palisading necrosis. The tumor showed an area of intense desmoplasia where tumor cells were surrounded by dense reticulin fibers. The desmoplastic cerebral tumors in children may be a distinct group of brain tumor, and it is important to understand the entity of these tumors which generally seem to be associated with more favorable prognosis compared to other high grade brain tumors.

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