Journal of Pathology and Translational Medicine

Volume 35(5); October 2001

Original Articles

The Expression of Extracellular Signal Regulated Kinase (ERK) in Non-Small Cell Lung Carcinoma.: Se Hoon Kim, Hyung Jung Kim, Young Nyun Park, Sang Ho Cho; Korean J Pathol. 2001;35(5):361-367.

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Abstract PDF: BACKGROUND
Although it was suggested that constitutive extracellular signal regulated kinase (ERK) activation plays a pivotal role in intracellular signal transduction related to oncogenesis, a consistent relationship between constitutive ERK activation and oncogenesis has not yet been clearly demonstrated. The purpose of this study is to evaluate the expression frequencies and pattern of phosphorylated ERK (p-ERK) in the non-small cell lung carcinoma (NSCLC) and to evaluate whether p-ERK is a useful prognostic factor.
METHODS
One hundred sixty cases of NSCLC tissue specimens were investigated by immunohistochemical staining for p-ERK. Clinicopathologic values (tumor stage, cell type, differentiation and presence of metastasis) and p-ERK expression of normal alveolar pneumocytes around NSCLC were compared with the incidence of tumor p-ERK expression.
RESULTS
Fifty-three out of 160 cases (33%) of NSCLC showed expression of p-ERK. There was no statistical correlation between the expression of p-ERK in the NSCLC neoplastic cells and the corresponding tumor stage, cell type and presence of metastasis. There was statistical significance between the expressions of p-ERK in alveolar pneumocytes around NSCLC (odds ratio: 6.130).
CONCLUSIONS
Based on these results, we suggest that p-ERK expression is not useful in predicting the prognosis of NSCLC. In regard to the theory of "field cancerization" and the phenomenon of "allele-specific loss or allele-specific mutations", the statistically significant p-ERK expression in alveolar pneumocytes around NSCLC suggests that constitutive ERK activation is involved in the early stage of NSCLC carcinogenesis rather than in proliferation, differentiation or metastasis of NSCLC.

Relationship between Epstein-Barr Virus (EBV), Apoptosis and Lymphocytic Infiltration in Gastric Carcinoma with Lymphoid Rich Stroma.: Tae Heon Kim, Mee Yon Cho, Sang Yeop Yi, Woo Hee Jung, Kwang Hwa Park; Korean J Pathol. 2001;35(5):368-375.

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Abstract PDF: BACKGROUND
Gastric carcinoma with lymphoid rich stroma (GCLRS) is an undifferentiated gastric carcinoma with heavy lymphocytic infiltrate. In order to clarify the relationship between lymphocytic infiltration and apoptosis in gastric carcinoma, we investigated the association of apoptosis with apoptotic proteins and Epstein-Barr Virus (EBV) expression in GCLRS.
METHODS
We performed immunohistochemical stains for bcl-2, bax and in situ hybridization for EBER (Epstein-Barr virus encoded RNA)-1 and the terminal deoxynucleaotidil transferase mediated dUTP-digoxigenin nick end labelling (TUNEL) technique using 47 out of 1635 gastric carcinoma cases.
RESULTS
The prevalence of GCLRS was 1.47% (24/1635). The prevalence of EBV involvement in GCLRS (79%, 19/24) was significantly higher than that of gastric carcinoma with lymphoid poor stroma (GCLPS) (8.7%, 2/23). The immunohistochemical stain for bcl-2 revealed negative expressions in all cases, but that of bax was positive for in all cases. bax was significantly correlated with the apototic index (P<0.05). There was no statistical significance between lymphocytic infiltration and apoptosis. The lymphocytic infiltration significantly correlated with the expression of EBV (P<0.05) but not with survival rate and apoptosis. However, most of the GCLRS displayed low clinical stages(stage IA, B), and we suggest that was a proper reason for a good prognosis.
CONCLUSIONS
These results support that EBV is associated with GCLRS, and there is no relationship between apoptosis and bcl-2, bax and prognosis. They also suggest that EBV infection play an important role in the gastric carcinogenesis.

beta-Catenin Expression in Gastric Carcinogenesis.: Haeyoun Kang, Yon Rak Choi, Hoguen Kim; Korean J Pathol. 2001;35(5):376-382.

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Abstract PDF: BACKGROUND
The molecular pathogenesis of gastric carcinoma is not yet well characterized. The purpose of this study is to assess the role of beta-catenin in gastric carcinogenesis.
METHODS
We analyzed beta-catenin expression using immunohistochemistry on 68 gastric adenomas and 34 gastric adenocarcinomas, and compared the result with pathological and molecular types of tumors and E-cadherin expression.
RESULTS
Nuclear expression of beta-catenin was noted more frequently in gastric adenomas than in carcinomas (40% vs. 21%, 0.05< or = P<1). There was no significant relationship between nuclear beta-catenin expression and histologic degree of adenoma, histologic type of carcinoma or microsatellite instability. E-cadherin expression showed significantly more frequent decrease in the membrane stainability of carcinomas compared to adenomas (P<0.01).
CONCLUSIONS
The frequent nuclear beta-catenin expression in gastric adenomas suggests that the beta-catenin alteration might play an early role in gastric carcinogenesis.

Expression of Fas/Fas Ligand and Its Relationship with Apoptosis in Chemically Induced Preneoplastic Lesions in Rat Liver.: Hye Jin Lee, Do Youn Park, Kyung Un Choi, Jee Yeon Kim, Chang Hun Lee, Mee Young Sol, Kang Suek Suh; Korean J Pathol. 2001;35(5):383-390.

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Abstract PDF: BACKGROUND
Apoptosis of hepatocytes plays a major role in experimental hepatocarcinogenesis of rats. But sequential change and localization of Fas and Fas ligand (FasL) in preneoplastic lesions and the relationship with apoptosis are not clearly elucidated.
METHODS
We investigated sequential change and localization of Fas/FasL and its relationship to apoptosis in preneoplastic lesions of chemical hepatocarcinogenesis in rats using northern blot analysis, immunohistochemistry and terminal deoxynucleotidyl transferase end labeling (TUNEL) assay.
RESULTS
We found that mRNA of Fas and Fas ligand increased for up to 42 days and 14 days after partial hepatectomy, respectively, and thereafter decreased with time. Fas protein was localized on the cytoplasm of hepatocytes of preneoplastic lesions, as well as on the cytoplasmic membrane of the adjacent liver parenchyme. Fas negative preneoplastic lesions were evident at 42 days after partial hepatectomy. FasL protein was found only in the cytoplasm of hepatocytes of preneoplastic lesions, instead of in the adjacent liver parenchyme. FasL-positive hepatocytes increased with time for up to 14 days after partial hepatectomy and therafter decreased. Also, TUNEL-positive apoptotic cells increased with time and were more numerous in the adjacent liver parenchyme than in the preneoplastic lesions.
CONCLUSIONS
It was suggested that Fas/FasL-mediated apoptosis might be one of the major mechanisms for controlling apoptotic cell death in the promotion stage of chemical hepatocarcinogenesis.

Early Detection of Metastasis by Immunohistochemistry in Uterine Cervical Carcinoma.: Kwan Kyu Park, Sun Young Kwon, Eun Sook Chang, Moon Young Jegal, Sang Mi Han, Soon Do Cha, In Sook Han; Korean J Pathol. 2001;35(5):391-340.

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Abstract PDF: BACKGROUND
Adhesion molecules are important in the maintenance of normal epithelial structure, and altered expression of these molecules may be important in epithelial tumors, particularly in the processes of invasion and metastasis.
METHODS
We have examined the expression of E-cadherin, cathepsin-D, CD44, CD44v6, nm23 and transforming growth factor-1 (TGF-1) proteins in the cervical squamous cell carcinoma to evaluate the prognostic significance of these molecules.
RESULTS
Immunostain for E-cadherin was highly expressed in the majority of cases of cervical carcinomatous lesions (85.7-100%), but cathepsin-D was very low (7.1-32%). Immunostain for CD44 showed a lower expression in invasive carcinoma with and without metastasis (50.4 and 52.2%) than in carcinoma in situ (68.0%). CD44v6 protein showed some controversy of expression between invasive carcinoma with metastasis (35.7%) without metastasis (56.5%). Staining for nm23 was observed in the high expression of invasive lesions (85.7%). TGF-1 and C-erbB-2 protein were highly expressed, especially in the microinvasive carcinoma (81.8%, 42.8%, respectively).
CONCLUSIONS
These results suggest that CD44 and CD44v6 were not highly expressed in the invasive squamous carcinoma of the uterine cervix. However, it is notable that TGF-1 and c-erbB-2 in the microinvasive carcinoma and nm23 in invasive carcinoma were highly expressed compared to these of the other lesions of the uterine cervix.

Microvessel Density and Expressions of bcl-2, p53, and Vascular Endothelial Growth Factor in Endometrial Carcinoma.: Soon Young Kim, Hae Jin Jeong, Myeng Sun Park, Bang Hur; Korean J Pathol. 2001;35(5):401-407.

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Abstract PDF: BACKGROUND
Recent studies have shown that oncogenes and tumor suppressor genes are involved in tumorigenesis and tumor progression. The inverse role of bcl-2 and p53 in endometrial carcinomas has been debated. Moreover, their roles in angiogenesis as well as the interrelationship between prognostic clinico-pathological factors and angiogenesis have not been elucidated in endometrial carcinomas.
METHODS
The expression rates of bcl-2, p53 and vascular endothelial growth factor (VEGF) in thirty-eight cases of surgically removed endometrial carcinomas were investigated using an avidin-biotin complex method of immunohistochemistry. CD34 immunostain for microvessel density (MVD) was also performed.
RESULTS
The expression rate of bcl-2 was higher in the endometrioid type carcinoma (43.8%) than in the non-endometriod type carcinoma (16.7%). There was a significantly increased bcl-2 expression in grade I compared to grades II and III (P<0.05). The p53 expression rate was significantly higher in the non-endometriod type carcinoma than in the endometrioid type carcinoma (P<0.05).The VEGF expression rate was higher in the non-endometriod type carcinoma (83.3%) than in the endometrioid carcinoma (28.1%). Differences of MVD according to stages, histological types, grades and bcl-2, p53 and VEGF expressions were not noted.
CONCLUSIONS
The expression rate of bcl-2 increases in the low grade endometrial carcinoma more than in the high grade one, so it may be suggested that bcl-2 expression could be used for an ancillary prognosticator. However, p53 and VEGF expressions and microvessel density may not have any prognostic value.

Immunohistochemical Study of Calponin, Smooth Muscle Myosin Heavy Chain, Cytokeratin 34E12, and p53 in Papillary Neoplasm of the Breast.: Jaejung Jang, In Ae Park; Korean J Pathol. 2001;35(5):408-415.

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Abstract PDF: BACKGROUND
The most important feature distinguishing intraductal papilloma (IDP) from papillary carcinoma is the presence of uniform myoepithelial cells (MECs) within the lesion.
METHODS
Immunohistochemistry (IHC) for calponin, smooth muscle myosin heavy chain (SMMHC), cytokeratin 34E12, and p53 were performed on 37 IDP, 4 intraductal papillary carcinomas (IDPCA), 5 microinvasive papillary carcinomas, and 5 invasive papillary carcinomas (IPCA), respectively.
RESULTS
The mean age of the patients was 43 (43.3+/-11.6) years. Cytokeratin 34E12 was expressed in epithelial cells (84%) as well as in MECs (23%) of IDP. The expression of SMMHC was significantly reduced in the intraductal and invasive papillary carcinoma (p=0.001). The expression of calponin was also significantly reduced (P<0.001) as IDP 95%, IDPCA 76%, microinvasive papillary carcinoma 39%, and IPCA 8%, respectively. p53 over-expression was noted in 3 (one IDP and two IPCA) of 51 cases.
CONCLUSIONS
Because MECs were significantly reduced with malignant progression, calponin and SMMHC were very useful markers for differentiating between benign and malignancy in the papillary neoplasm. Calponin was more sensitive than SMMHC and was an excellent ancillary test for assessing MECs and for detecting microinvasion.

Expression of pRb, p16, Cyclin D1 and Cyclin E in Infiltrating Duct Carcinoma of the Breast.: Hea Kyoung Hur, Mee Sook Roh, Jin Sook Jeong, Seo Hee Rha, Gi Yeong Huh, Sook Hee Hong; Korean J Pathol. 2001;35(5):416-423.

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Abstract PDF: BACKGROUND
Inactivation of the retinoblastoma protein (pRb) is a mechanism by which tumor cells can subdue normal growth control. Among the molecules involved in control of pRb phosphorylation, cyclin D1 and cyclin E have been found to be deregulated and overexpressed in various types of cancers.
METHODS
Immunohistochemical stains for pRb, p16, cyclin D1 and cyclin E were performed in 73 cases of infiltrating duct carcinomas of the breast. In addition to analysis of their expression rates, the relationships between their expressions and the clinicopathologic parameters were evaluated.
RESULTS
pRb, p16, cyclin D1 and cyclin E were positive in 64.7% (44 out of 68 cases), 24.6% (15 out of 61 cases), 43.8% (32 out of 73 cases) and 61.6% (45 out of 73 cases), respectively. Their expression rates were not significantly associated with clinicopathologic prognostic factors. 33 out of 38 cases with p16-negative reactions were pRb positive, while 10 out of 15 cases with pRb-negative reactions were p16 positive. There was a significant inverse relationship between pRb and p16 expressions (P<0.005). 25 out of 32 cases with cyclin E-positive reactions were cyclin D1-positive, and 25 out of 45 cases with cyclin D1-positive reactions were cyclin E-positive. A statistically significant association was observed between cyclin D1 and cyclin E expressions (P<0.05).
CONCLUSIONS
The main mechanism during tumorigenesis of breast carcinoma depends on the cyclin D1/p16/pRb pathway, but cyclin E might play a role in the absence of cyclin D1. The inverse correlation between the pRb and p16 expressions may represent one of the important mechanisms in tumorigenesis, as well.

The Effect of Antibody and Gene Therapy for Transforming Growth Factor- 1 on Scar Formation.: Jun Hyung Kim, Ki Hwan Han, Jong Duck Ahn, In Kyu Lee, Eun Joo Kim, Mee Yul Hwang, Kwan Kyu Park; Korean J Pathol. 2001;35(5):424-432.

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Abstract PDF: BACKGROUND
Transforming growth factor (TGF)- has a large variety of biological functions, including the modulation of inflammation and the immune system, and is presumed to play important roles in repairing wounds and reducing scarring. The objective of this study is to examine the effects of TGF-1 on healing wounds and reducing scarring. We have also analysed the ability of the hemagglutinating virus of Japan (HVJ) liposome mediated antisense oligodeoxynucleotides (ODNs) to specifically inhibit wound-induced expressions of TGF-1 proteins and mRNA in the rat skin.
METHODS
Skin wounds were created on the backs of 80 anesthetized rats. The first group of wounds, as the controls, was unmanipulated. The second group of wounds, as positive controls or an excessive scarring model, was injected with TGF-1 subcutaneously. The third group of wounds was injected with anti-TGF-1 antibody subcutaneously. The fourth group of wounds was injected with HVJ liposome mediated antisense ODNs for TGF-1 subcutaneously. The wounds of all groups were bisected and analysed histologically 5, 10, 15, 30, and 50 days after the wounds were made.
RESULTS
All control wounds (TGF-1 or no injection) healed with scarring, whereas the wounds treated with the antibody or antisense ODNs healed with less scar formation compared to the control group. The wounds treated with the antibody or antisense ODNs had fewer macrophages, less collagen and fibronectin contents than the other wounds. Northern blotting and in situ hybridization analysis showed that wound sites treated with HVJ liposome mediated antisense ODNs for TGF-1 exhibited decreased levels of TGF-1 mRNA after injury.
CONCLUSIONS
These findings suggest an important new approach to controlling scarring in normal wound healing, complementing the practice of adding exogenous growth factors to chronic wounds in the attempt to inhibit collagen deposition.

Immunohistochemical Expression of Synaptophysin in Brain Tumors.: Byung Ha Choi, Shin Kwang Khang; Korean J Pathol. 2001;35(5):433-439.

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Abstract PDF: BACKGROUND
Perikaryal or perikaryal surface immunostaining for synaptophysin has been posited to distinguish the neoplastic neuronal elements of gangliogliomas from entrapped non-neoplastic neurons in other gliomas of various types. However, recent studies revealed that perikaryal surface immunoreactivity can be seen in the neurons of normal human spinal cords and brains, as well as in the brain tissues around certain non-neuronal lesions. To access the validity of this criterion in the diagnosis of ganglion cell neoplasms, we evaluated patterns of immunostaining of synaptophysin in neuronal, glial and some non-neuroepithelial tumors.
METHODS
We selected 104 cases of gangliogliomas, gangliocytomas, central neurocytomas, dysembryoplastic neuroepithelial tumors, astrocytomas, oligodendrogliomas, glioblastomas, a pleomorphic xanthoastrocytoma, meningiomas, arterio-venous malformations, craniopharyngiomas, a foreign body granuloma, temporal lobe epilepsies, and autopsied brains. A representative block including the gray matter was identified for each case, and synaptophysin immunostaining was performed.
RESULTS
Perikaryal and perikaryal surface immunoreactivity for synaptophysin was observed in the neurons of various types of lesions. Percentage of perikaryal and perikaryal surface immunoreactivity of the gangliogliomas, glial tumors, and non-neuroepithelial lesions were 100%/93%, 80%/58% and 57%/26%, respectively.
CONCLUSIONS
Although synaptophysin positive neurons are found in the ganglioglioma, these patterns are clearly not pathognomonic for glioneuronal tumors.

Case Reports

Small Cell Carcinoma of the Ovary, Hypercalcemic Type, Large Cell Variant.: Jong Sil Lee, Jong Hak Lee, Yu Kyung Kim, Sun Hoo Park, Gyung Hyuck Ko; Korean J Pathol. 2001;35(5):440-443.

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Abstract PDF: We report the clinical and pathological features, including the immunohistochemical and electron microscopic findings, of a case of hypercalcemic type, large cell variant, ovarian small cell carcinoma. A 44-year-old woman complained of abdominal pain and dysmenorrhea. A mass on the left ovary was detected by computer tomographic scan. A total hysterectomy with bilateral salpingo-oophorectomy was done. Histologically, the tumor was predominantly composed of large cells with abundant eosinophilic cytoplasm and prominent nucleoli. Mucin-containing cells and myxoid stroma were also present. Typical follicle-like spaces with lined by small, closely packed epithelial cells with scanty cytoplasm were occasionally seen. No dense core granules were identified on electron microscopic examination.

Primary Carcinosarcoma of the Skin.: Mee Sook Roh, Gi Yeong Huh, Sook Hee Hong; Korean J Pathol. 2001;35(5):444-446.

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Abstract PDF: Carcinosarcoma is a biphasic tumor composed of intimately admixed malignant epithelial and mesenchymal components. Primary cutaneous cases are extremely rare; there are with only 18 cases documented in English literature to date. We present a case of a 55-year-old woman with a primary carcinosarcoma of the scalp. Histologically, the lesion consisted of an undifferentiated spindle cell sarcomatous component admixed with a resembling malignant tumor with eccrine differentiation. Immunohistochemistry showed the epithelial component to express cytokeratin and EMA and lack of vimentin expression. In the sarcomatous component, the staining pattern demonstrated the reverse. The patient received adjuvant radiotherapy; but one month later a recurring nodule developed at this site, and two months later, metastasis to the neck lymph node developed. There is no evidence of recurrence or metastasis after 25 months of follow-up.

Dendritic Myxofibrolipoma.: Sung Nam Kim, Kye Hyun Kwon, Yeon Lim Suh; Korean J Pathol. 2001;35(5):447-450.

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Abstract PDF: Dendritic myxofibrolipoma is a recently described disease entity that represents a distinctive benign soft tissue neoplasm showing the combined features of spindle cell lipoma and the solitary fibrous tumor. Immunohistochemical stains reveal a strong positivity for vimentin, CD34 and bcl-2, which highlight the dendritic nature of the tumor cells by demonstrating slender complex cytoplasmic prolongations. There have been 12 cases of dendritic myxofibrolipomas reported in literature. In Korea, none of the cases have been described. We report such a case with a 28-year-old man who had a palpable subcutaneous mass on his right shoulder for 4 months. Grossly, the removed mass measured 11X7X5 cm and appeared to be a well-encapsulated, lipomatous tumor with marked myxoid appearance. Microscopically, this tumor consisted of spindle cells admixed with dense collagen fibers and mature adipocytes in abundant myxoid stroma with high vascularity. Immunohistochemically, the tumor cells were strongly reactive for vimentin and CD34 and weakly reactive for bcl-2, and negative for S-100 protein.

Desmoplastic Small Round Cell Tumor of the Sigmoid Colon.: Kwang Il Kim, Jung Yeol Kim, Insun Kim; Korean J Pathol. 2001;35(5):451-454.

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Abstract PDF: Desmoplastic small round cell tumor (DSRCT) is a distinctive disease with a multidirectional differentiation and an aggressive clinical course. It mostly occurs in mesothelial-lined sites, and tumors originating in the paratesticular region, pleura and central nervous system are rarely reported. We report a case of DSRCT occurring in the sigmoid colon of a 39-year-old man, which was difficult to distinguish from small cell neuroendocrine carcinoma. The tumor was characterized by small round cells with irregular nests, cords, or rosette-like structures in the striking desmoplastic stroma. Some tumor cells had a rhabdoid feature with eosinophilic cytoplasmic globules. The tumor cells showed immunoreactivity for cytokeratin, epithelial membrane antigen, vimentin, desmin, neuron-specific enolase and Leu-7. Electron microscopic finding revealed perinuclear globoid whorls of intermediate filaments pushing the nucleus eccentrically.

Rasmussen's Encephalitis.: Na Rae Kim, Han Jae Joon, Yeon Lim Suh, Moon Hyang Lee; Korean J Pathol. 2001;35(5):455-460.

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Abstract PDF: We herein report a case of intractable epilepsy that occurred in a 7-year-old girl, which is consistent with radiological and clinicopathological hallmarks of Rasmussen's encephalitis. The patient showed characteristic primary unilateral involvement with secondary bilateral propagation. Microscopically, the cortical atrophy due to neuronal loss, intense GFAP-immunoreactive astrogliosis, neuronophagia, perivascular lymphocytic infiltration and microglial nodules was seen throughout the cortex and white matter. No viral inclusions were noted; no cytomegalovirus, herpes simplex virus or Epstein-Barr virus was found by in situ hybridization. Granular immunofluorescence for C4, C1q and IgG within the blood vessel walls was noted, and ultrastructurally, only nonspecific vascular injury was found. Rasmussen's encephalitis is a diagnosis of exclusion; it can be diagnosed by the combination of clinical manifestation, neuroimaging and characteristic pathologic features.

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