Journal of Pathology and Translational Medicine

Volume 37(1); February 2003

Original Articles

Expression of Matrix Metalloproteinase (MMP)-2, MMP-9, Tissue Inhibitor of Metalloproteinase (TIMP)-1 and TIMP-2 in Adenocarcinomas of The Gallbladder.: Jong Yup Bae, Jinsub Choi, Hyun Cheol Chung, Chanil Park, Young Nyun Park; Korean J Pathol. 2003;37(1):1-9.

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Abstract PDF: BACKGROUND
Matrix metalloproteinase (MMP)-2 and MMP-9 degrade type IV collagen and are antagonized by the tissue inhibitors of metalloproteinase (TIMP)-2 and TIMP-1, respectively.
METHODS
We studied by immunohistochemistry the expressions of MMP-2, MMP-9, TIMP-1 and TIMP-2 in 72 cases of adenocarcinoma of the gallbladder.
RESULTS
The MMP-2, MMP-9 and TIMP-1 expressions were significantly higher in well/moderately differentiated adenocarcinomas than in poorly differentiated adenocarcinomas, in adenocarcinomas that had invaded the lamina propria/proper muscle than in those that had invaded the perimuscular connective tissue or beyond the serosa, and in adenocarcinomas with fungating growth than in those with infiltrative growth. The TIMP-2 expression showed a similar pattern without statistical significance. Regarding the status of lymph node metastasis, the MMP-2 expression was significantly higher in cases without lymph node metastasis. The MMP-2 and MMP-9 expressions were significantly related to those of TIMP-2 and TIMP-1, respectively, with regard to depth of invasion, differentiation, and growth patterns of the adenocarcinomas.
CONCLUSIONS
MMP-2, MMP-9, TIMP-1 and TIMP-2 are suggested to play important roles in the progression to early invasion of adenocarcinomas, in which the function of MMP-2 is inhibited by TIMP-2.

Immunoexpressions of Thyroid Transcription Factor-1 and bcl-2 in Congenital Cystic Adenomatoid Malformation.: Na Rae Kim, Dong Hoon Kim, Gou Young Kim, Dae Shick Kim, Joungho Han; Korean J Pathol. 2003;37(1):10-14.

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Abstract PDF: BACKGROUND
Congenital cystic adenomatoid malformation (CCAM) is a congenital abnormality of branching morphogenesis of the lung. Thyroid transcription factor-1 (TTF-1) is detected in human respiratory epithelial cells from 11 weeks of gestation, and at full term, TTF-1 expression is confined within type II epithelial cells and in some respiratory nonciliated bronchiolar epithelial cells. Immunoexpression of bcl-2 is intimately related to apoptosis during the development.
METHODS
To elucidate the nature of the lesion, TTF-1 expression was evaluated in twenty-four cases of CCAM (eight cases of type 1 and sixteen cases of type 2) along with immunostaining for bcl-2. For the control group, four cases of fetal lungs (19 week-, 21 week-, 27 week- and 40 week-gestational age) were also evaluated. In all cases of CCAM, TTF-1 was detected in the nuclei of epithelial cells lining the cysts.
RESULTS
TTF-1 was expressed in the majority of the bronchiolar-like epithelial cells of the cysts in CCAM types 1, and 2, where almost 100% of the lining cells of the cysts were TTF-1 positive with variable intensity, while negative TTF-1 expressions were found in the alveolar-like epithelium of the adjacent alveoli or distal nonciliated bronchi. For bcl-2 immunostaining, no lining epithelial cells of the cysts were stained except for the infiltrating lymphocytes. In the control group, strong immunoreactivities found in early fetal stages were absent in the full-term aged lung (40 gestational weeks).
CONCLUSION
These results support the hypothesis that CCAM types 1 and 2 reflect the abnormalities in lung morphogenesis and differentiation that are distinct from those for normally developed alveolar epithelium or adjacent bronchial epithelium, thus retaining the abnormal TTF-1 immunoreactions. Though restricted to CCAM types 1 and 2 in this study, CCAM might be related to TTF-1 rather than apoptosis in the morphogenesis of the developing lung.

Relationships between Types of Proximal Gastric Mucosa and Clinicopathological Features.: Jong Sil Lee, Hwal Woong Kim, Jeong Hee Lee, Hee Shang Youn, Woon Tae Jung, Gyung Hyuck Ko; Korean J Pathol. 2003;37(1):15-18.

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Abstract PDF: BACKGROUND
It has been believed that there is a pure mucus-secreting cardiac mucosa (CM), about 2 cm in length, below the gastroesophageal junction. However, recent reports suggest that CM might not be located at the most proximal portion of the stomach. The purpose of this study is to investigate the relationships between the types of proximal gastric mucosa and patients' age, sex, their condition regarding the Helicobacter pylori infection, and severity of chronic gastritis.
METHODS
Two pieces of mucosal tissue from the most proximal portion of the stomach and the antrum of 44 pediatric and 85 adult patients were examined using a light microscope. A rapid urease test was performed on the other antral specimen from each patient.
RESULTS
In 46 (90.2%) out of 51 patients with aged 30 or under, only the pure acid-secreting oxyntic mucosa (OM) was present at the most proximal portion of the stomach. The cardiac or mixed oxyntocardiac mucosa (OCM) increased in prevalence with age. The CM or OCM was found more frequently in patients with H. pylori infection or severe gastritis than in those without H. pylori infection or those with mild gastritis. However, there were no statistically significant differences within the same age groups.
CONCLUSIONS
Although the OCM is sometimes present at the most proximal portion of the stomach, the CM is absent or rare in individuals under the age of 30. The OCM or CM increases in prevalence with age. There are no direct relationships between the type of proximal gastric mucosa and a patient's gender, his/her condition regarding the H. pylori infection, and severity of chronic gastritis.

Relationship between Expression of Anaphase-promoting Complex and Prognostic Factors in Invasive Ductal Carcinoma of Breast.: Minseob Eom, Kwang Hwa Park, Kwang Gil Lee, Sang Yeop Yi, Yup Kang, Soon Hee Jung; Korean J Pathol. 2003;37(1):19-25.

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Abstract PDF: BACKGROUND
The role of the anaphase-promoting complex (APC) is to promote the degradation of mitotic cyclins and other substrates involved in sister chromatid adhesions. The APC appears to be responsible for the degradation of cyclin B and may have a potential role in the loss of control concerning cell proliferation in mammalian cells. However, a direct link between the defects in the APC components and oncogenesis has not been estabilished. This study investigates the relationship between APC expression and variable prognostic factors in invasive ductal carcinoma of the breast.
METHODS
We evaluated 108 cases of invasive ductal carcinoma surgically resected from January, 1996 to May, 2000 at Wonju Christian Hospital, Wonju College of Medicine, Yonsei University. Immunohistochemical stains for APC, estrogen receptor, and Ki-67 were done in paraffin sections using the avidin-biotin complex method. The results were compared with clinical and pathologic parameters and flow cytometric DNA analysis factors.
RESULTS
Forty cases (37.0%) showed immunopositive reactions for APC. The APC positivity in histologic grades 1, 2, and 3 were 28 cases (84.4%), 33 cases (60.0%), and 7 cases (35.0%), respectively (p=0.0011). The APC expressions in cases with the number of mitosis of less than 10, 10-19, and more than 20 per 10 high power fields, were noted in 37 cases (75.5%), 26 cases (63.4%), and 5 cases (27.8%), respectively (p=0.0016). The mean value of the Ki-67 labeling index was 221.7 in the APC-positive group and 317.9 in the APC-negative group (p= 0.0091). DNA flow cytometric analysis revealed higher APC expressions in cases with diploid patterns (p=0.0095). The APC expression rate increased significantly with decreasing histologic grade, with decreasing mitotic activity, in cases with a low Ki-67 labeling index, and those in the diploid group (p<0.05). The APC expression was not statistically correlated with clinical stage, tumor size, and estrogen receptor status.
CONCLUSIONS
These findings suggest that positive APC expression may be considered as a good prognostic factor of invasive ductal carcinoma, and loss of APC expression may be related with the progression of breast cancer.

HER-2/neu Oncogene Amplification by Chromogenic in situ Hybridization and Immunohistochemical Expression of Topoisomerase II-alpha in the Breast Cancer.: Tae Jin Lee, Hyung Goon Oh, Gui Young Kwon, Mi Kyung Kim, Eon Sub Park, Jae Hyung Yoo; Korean J Pathol. 2003;37(1):26-34.

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Abstract PDF: BACKGROUND
Amplifications of the HER-2/neu oncogene and the Topoisomerase II-alpha gene are important determiners of the response to chemotherapy in the breast cancer. For detecting HER-2/neu amplification, fluorescent in situ hybridization and immunohistochemistry are currently regarded as standard methods. Chromogenic in situ hybridization (CISH) is investigated as a new modification of in situ hybridization. The purpose of this study is to compare the efficacy of CISH and immunohistochemistry (IHC) in detecting HER-2/neu oncogene amplification and to investigate the prognostic significance of the HER-2/neu oncogene and the Topoisomerase II-alpha gene in breast cancer.
METHODS
Using CISH and IHC the amplifications and protein expressions of the HER-2/neu oncogene were studied on paraffin sections of 43 infiltrating duct carcinomas. The expression of the Topoisomerase II-alpha gene was studied immunohistochemically.
RESULTS
Of the 43 infiltrating duct carcinomas, amplifications of the HER-2/neu oncogene by CISH were observed in 8 cases (18.6%), and the HER-2/neu protein was deemed overexpressed by IHC in 9 cases (20.9%). The amplifications of the HER-2/neu oncogene showed a statistically significant correlation with tumor size, histological grade, and the Topoisomerase II-alpha index. The Topoisomerase II-alpha index showed a statistically significant correlation with tumor size, lymph node status, stage, histologic grade, and estrogen receptor status.
CONCLUSIONS
CISH is a useful alternative for determining HER-2/neu amplification, especially for confirming the immunohistochemical staining results. HER-2/neu amplification and the Topoisomerase II-alpha gene index may be prognostic factors of breast cancer.

Expression of p53 and Vascular Endothelial Growth Factor mRNA in Angiogenesis of Non-Small Cell Lung Carcinoma.: Jun Seog Kim, Tae In Park, Myoung Hoon Lee, Eun Kyoung Kwak, Ji Young Park, Jung Sik Kwak, Jong Min Chae; Korean J Pathol. 2003;37(1):35-40.

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Abstract PDF: BACKGROUND
Angiogenesis is one of the most important factors in the progression and me-tastasis of malignancies. Angiogenesis is a multistep process requiring the interaction of numerous factors able to stimulate the growth and development of new vessels. But, understanding of the mechanism involved in VEGF expression is unclear.
METHODS
Expressions of p53 and VEGF, and neovasculiarization were examined in 19 cases of surgically resected non-small cell carcinoma of the lung by the immunohistochemical staining. Furthermore, VEGF mRNA expressions were quantified in all cases using the real-time quantitative RT-PCR. These results were compared with clinicopathologic parameters such as histologic grade and stage.
RESULTS
Tumors with high aberrant p53 expressions showed significantly higher VEGF mRNA ex-pressions and microvessel counts than those with low p53 expressions. Expressions of p53 as well as VEGF and micovessel counts were closely associated with the tumor stage, but not with the histologic grade and other clinical parameters.
CONCLUSIONS
These results suggest that aberrant p53 expression may play a role in the regulation of VEGF expression and may be involved in controlling angiogenesis in non-small cell carcinoma of the lung.

Apoptosis and Cell Proliferation in Experimental Acute Tubular Necrosis Induced by Intramuscular Glycerol Injection.: Wan Seop Kim, Jung Woo Noh, Moon Hyang Park; Korean J Pathol. 2003;37(1):41-49.

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Abstract PDF: BACKGROUND
Acute tubular necrosis (ATN) is the most common cause of acute renal failure. It is characterized by the destruction of tubular epithelial cells. To examine apoptosis and proliferative activity of tubular cells in the course of acute tubular necrosis, we induced acute renal failure by intramuscular hypertonic glycerol injection to New Zealand White rabbits.
METHODS
The immunohistochemistry was done for Ki-67 and tissue-transglutaminase (tTG), and the terminal deoxynucleotidyl transferase mediated nick end labeling (TUNEL) method was performed using a total of 77 renal specimens including 29 gun biopsies and 48 nephrectomiy specimens.
RESULTS
Widespread tubular injury with pigment casts and interstitial hemorrhage were noted. The tubular proliferation index was increased at 2 hours after glycerol injection, and the index peaked at 3 hours. The second cell proliferation peak was noted at 3 days. Apoptotic cells were identified by TUNEL and tTG staining. The apoptotic index was significantly increased, and it peaked at 24 hours after glycerol injection. There was a significant correlation between the proliferation index (MIB-1) the and the apototic index (TUNEL)(p= 0.001). A DNA ladder pattern was observed at 6 to 8 hours.
CONCLUSIONS
Tubular cell proliferation and apoptosis occur in the early phase after the induction of acute tubular necrosis, and the excess hyperplastic epithelial cells appear to be eliminated by apoptosis.

Undifferentiated Sarcoma of the Liver: Clinical and Pathologic Study of 9 Cases.: Kyung Chul Moon, Chong Jai Kim, Je G Chi, Gyeong Hoon Kang; Korean J Pathol. 2003;37(1):50-57.

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Abstract PDF: BACKGROUND
Undifferentiated sarcoma of the liver (USL) is a rare malignant tumor that is found in children and young adults.
METHODS
We performed a clinicopathologic analysis of 9 cases (M:F=4:5) of USL using immunohistochemical staining for vimentin, desmin, -smooth muscle actin (SMA), CD68, CD117, S-100, cytokeratin, epithelial membrane antigen (EMA), and p53.
RESULTS
Grossly, the tumors were large, single, and well demarcated with areas of hemorrhage and necrosis. Microscopically, the tumors were composed of spindle to stellate cells and variable numbers of multinucleated giant cells with a myxoid background. The tumors had eosinophilic globules, small cystic spaces and fibrous pseudocapsule. Under immunohistochemical study, the tumor cells were positive for vimentin, CD68 and desmin, but negative for S-100 protein. p53 overexpression was noted in most cases, and four cases showed immunoreactivity for CD117. All patients received chemotherapy before or after the excision of the tumors. Two patients died during chemotherapy, but six patients survived without recurrence for 18, 35, 53, 57, 65 and 126 months after the initial diagnosis. The remaining one patient survived with recurrence for 20 months after the initial diagnosis.
CONCLUSION
Our cases showed unique pathological and immunohistochemical features similar to the cases of previous reports. In contrast to the previous reports, the outcome of our cases were not poor. Modern multimodal treatment including surgical resection combined with multiagent chemotherapy may contribute to the better prognoses.

Case Reports

Type 2 Fiber Predominance in Patients with Muscle Cramp and Exertional Myalgia: A Report of Three Cases.: Na Rae Kim, Sung Hye Park, Lim Suh Yeon, Byung Joon Kim; Korean J Pathol. 2003;37(1):58-61.

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Abstract PDF: Type 2 fiber predominance or a decrease of the type 1/type 2 ratio was rarely reported as the only abnormal pathologic finding in patients suffering from muscle cramp and myalgia. Here, we describe the clinicopathologic findings of three cases of type 2 fiber predominance, presented with muscle cramp and myalgia in otherwise healthy patients. All of them were young men (18, 19 and 22 years). Light microscopic and neurologic examinations, and laboratory data showed mere nonspecific findings that were not concordant with their subjective symptoms. However, enzyme histochemistry performed on muscle biopsy revealed an increased fraction of type 2 fibers; 73%, 80%, and 75%, in each case. The pathogenesis of this entity remains unclear, but the recognition of this unusual clinicopathologic entity is important for both pathologists and neurologists so they can avoid misdiagnoses or unnecessarily tiresome studies. We emphasize that type 2 fiber predominance should be included in the underlying causes of unexplained muscle cramps and exertional myalgia, especially among young adults, although it remains unclear whether the fiber type predominance is a separate entity or a part of other underlying neurologic or systemic disorders.

Metastasizing Atypical Chondroid Lesion: A Case Report.: Heejeong Lee, Jinyoung Yoo, Seok Jin Kang, Byung Kee Kim; Korean J Pathol. 2003;37(1):62-65.

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Abstract PDF: We recently experienced an atypical chondroid lesion metastatic to the lung. Examined under the microscope, the excised nodules displayed abundant amounts of chondroid tissue and necrosis with dystrophic calcification. The calcification had a characteristic "chicken wire" pattern. The chondroblasts contained one or two round to oval, focally indented nuclei with inconspicuous nucleoli. Although some enlarged nuclei with mild to moderate pleomorphism were present, significant nuclear atypia was lacking. Mitotic figures were scarce (1/10 high power field). Scattered multinucleated osteoclast-type giant cells were observed among the chondroblasts. Thus, the possibility of chondroblastoma was considered first. Metastasis of histologically benign chondroblastoma is a rare event, but well documented. The pulmonary metastatic nodules were described as ceasing to grow in some cases; and a significant number of patients were free of tumors following removal of the metastatic nodules. These findings suggest that the metastasis may represent a simple transport phenomenon. However, there are, as yet, no histologic parameters that help determine whether these metastases are to cease their growth or will progress to kill the host.

Gonadoblastoma Overgrown by Dysgerminoma in Women with 46,XX Karyotype: A Report of Two Cases.: Mi Jung Kim, Hee Jeong Ahn, Ji Young Kim, Kyu Rae Kim; Korean J Pathol. 2003;37(1):66-70.

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Abstract PDF: Gonadoblastoma is a neoplasm containing an intimate mixture of germ cells and elements resembling immature granulosa or Sertoli cells. It has been considered as in situ germ cell malignancy that can be overgrown by more malignant germ cell neoplasms. The tumor has been reported to almost exclusively develop in various types of gonadal maldevelopment syndromes containing the Y chromosome, such as in pure or mixed gonadal dysgenesis and, less commonly, in male hermaphroditism. However, occurrences in phenotypically and chromosomally normal, menstruating women are exceptionally rare. We report two cases of gonadoblastoma overgrown by dysgerminoma occurring in the ovaries of phenotypically and cytogenetically normal menstruating women. One of the two cases showed an area composed of granulosa cell tumor-like elements. This type of combination has been very rarely described, and exemplified that gonadoblastoma may progress to sex cord-stromal tumors as well as to the malignant germ cell tumors.

Uterine Leiomyoma with Massive Lymphocytic Infiltration.: Won Mi Lee, Moon Hyang Park; Korean J Pathol. 2003;37(1):71-73.

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Abstract PDF: Uterine leiomyoma with massive lymphocytic infiltration is known to be associated with Gona-dotropin releasing hormone (GnRH) agonist treatment. The lymphocytic cells in those cases were composed predominantly of T-lymphocytes. We report an unusual case of uterine leiomyoma with massive lymphocytic infiltration, composed predominantly of B-lymphocytes, without a history of GnRH agonist treatment. A 59-year-old woman underwent a transvaginal hysterectomy for uterine leiomyomas. Microscopically, the leiomyoma showed a massive infiltration of the lymphocytes, histiocytes, and also showed scattered plasma cells and many lymphoid follicles. The lymphocytic infiltrates were confined to the leiomyoma. These lymphocytic cells mainly represented the B-cell phenotype. She had no history of GnRH agonist treatment. To the best of our knowledge, This is the first reported case in Korea.

Localized Malignant Mesothelioma of Peritoneum Arising in the Liver Capsule: A Case Report.: Hae Joung Sul, Dae Young Kang; Korean J Pathol. 2003;37(1):74-77.

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Abstract PDF: Mesothelioma originates in several sites including the pleura, peritoneum, pericardium, and tunica vaginalis. The pleura is the most common site of origin, but cases originating in the per- itoneum is relatively rare. Mesothelial lesions of the peritoneum may pose significant diagnostic problems. Yet, the accurate identification of this lesion is important because of its distinctive behavior and treatment modality. We herein report a case of malignant mesothelioma of the peritoneum arising in the capsule of the liver. The accuracy of our diagnosis has been confirmed by the immunohistochemical study and electron microscopic examination.

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