Journal of Pathology and Translational Medicine

Review

Molecular Testing for Gastrointestinal Cancer: Hye Seung Lee, Woo Ho Kim, Yoonjin Kwak, Jiwon Koh, Jeong Mo Bae, Kyoung-Mee Kim, Mee Soo Chang, Hye Seung Han, Joon Mee Kim, Hwal Woong Kim, Hee Kyung Chang, Young Hee Choi, Ji Y. Park, Mi Jin Gu, Min Jin Lhee, Jung Yeon Kim, Hee Sung Kim, Mee-Yon Cho; J Pathol Transl Med. 2017;51(2):103-121. Published online February 19, 2017; DOI: https://doi.org/10.4132/jptm.2017.01.24

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With recent advances in molecular diagnostic methods and targeted cancer therapies, several molecular tests have been recommended for gastric cancer (GC) and colorectal cancer (CRC). Microsatellite instability analysis of gastrointestinal cancers is performed to screen for Lynch syndrome, predict favorable prognosis, and screen patients for immunotherapy. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved in metastatic CRCs with wildtype RAS (KRAS and NRAS exon 2–4). A BRAF mutation is required for predicting poor prognosis. Additionally, amplification of human epidermal growth factor receptor 2 (HER2) and MET is also associated with resistance to EGFR inhibitor in metastatic CRC patients. The BRAF V600E mutation is found in sporadic microsatellite unstable CRCs, and thus is helpful for ruling out Lynch syndrome. In addition, the KRAS mutation is a prognostic biomarker and the PIK3CA mutation is a molecular biomarker predicting response to phosphoinositide 3-kinase/AKT/mammalian target of rapamycin inhibitors and response to aspirin therapy in CRC patients. Additionally, HER2 testing should be performed in all recurrent or metastatic GCs. If the results of HER2 immunohistochemistry are equivocal, HER2 silver or fluorescence in situ hybridization testing are essential for confirmative determination of HER2 status. Epstein-Barr virus–positive GCs have distinct characteristics, including heavy lymphoid stroma, hypermethylation phenotype, and high expression of immune modulators. Recent advances in next-generation sequencing technologies enable us to examine various genetic alterations using a single test. Pathologists play a crucial role in ensuring reliable molecular testing and they should also take an integral role between molecular laboratories and clinicians.

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Original Articles

Transglutaminase 2 Expression and Its Prognostic Significance in Clear Cell Renal Cell Carcinoma: Min Jee Park, Hae Woon Baek, Ye-Young Rhee, Cheol Lee, Jeong Whan Park, Hwal Woong Kim, Kyung Chul Moon; J Pathol Transl Med. 2015;49(1):37-43. Published online January 15, 2015; DOI: https://doi.org/10.4132/jptm.2014.10.25

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Abstract PDF

Background
A few recent studies have demonstrated a possible role of transglutaminase 2 (TG2) in tumorigenesis or progression of renal cell carcinoma (RCC). The aim of this study was to examine TG2 expression and its clinicopathologic significance in a large number of human clear cell RCCs (CCRCCs). Methods: We analyzed 638 CCRCC patients who underwent partial or radical nephrectomy between 1995 and 2005. The expression of TG2 was determined by immunohistochemistry and categorized into four groups, according to staining intensity: negative (0), mild (1+), moderate (2+), and strong (3+). Results: TG2 staining intensity was negative in 8.5% of CCRCC (n=54), 1+ in 32.6% (n=208), 2+ in 50.5% (n=322), and 3+ in 8.5% (n=54). Strong TG2 expression was correlated with high Fuhrman nuclear grade (p=.011), high T category (p=.049), metastasis (p=.043) and male sex (p<.001) but not with N category.The survival analysis showed a significant association between strong TG2 expression and worse overall and cancer-specific survival (p=.027 and p=.010, respectively). On multivariate analysis, strong TG2 expression was a marginally significant prognostic indicator for Fuhrman nuclear grade and TNM staging (p=.054). Conclusions: Our study is the first to demonstrate the clinicopathologic significance of TG2 expression in a large number of human CCRCC samples. Strong TG2 expression was associated with high nuclear grade and poor prognosis.

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Transglutaminase 2 is associated with adverse colorectal cancer survival and represents a therapeutic target
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Distribution of Human Papillomavirus 52 and 58 Genotypes, and Their Expression of p16 and p53 in Cervical Neoplasia: Tae Eun Kim, Hwal Woong Kim, Kyung Eun Lee; Korean J Pathol. 2014;48(1):24-29. Published online February 25, 2014; DOI: https://doi.org/10.4132/KoreanJPathol.2014.48.1.24

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Abstract PDF

Background

This study investigates the prevalence of human papillomavirus (HPV) 52 and 58 genotypes among women residing in Busan, and the expression of p16 and p53 proteins in cervical neoplasia with HPV 52 and 58 infections.

Methods

A total of three hundred fifteen cases were analyzed using the HPV DNA chip test for HPV genotypes, and of these, we retrospectively examined p16 and p53 expression in 62 cases of cervical tissues infected with HPV 52 and 58 using immunohistochemistry.

Results

HPV 52 and 58 genotypes were identified in 62 (54.9%) out of 113 high-risk, HPV-infected cases. Of the cases examined, there were 19 single HPV 52 infections (16.8%), 23 single HPV 58 infections (20.4%), 4 multiple HPV 52 infections (3.5%), and 16 multiple HPV-58 infections (14.2%). Immunoreactivity of p16 and p53 was observed in 41 (66.1%) and 23 (37.1%) of the 62 cases of cervical neoplasia infected with HPV 52 and 58 genotypes, respectively.

Conclusions

This study demonstrates a high prevalence of HPV 52 and 58 genotypes, in addition to HPV 16, among high-risk strains of cervical neoplasia in Korea. These findings suggest that development of more vaccines would be beneficial for the prevention of the various HPV genotypes.

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Screening for High-Risk Human Papillomavirus Reveals HPV52 and HPV58 among Pediatric and Adult Patient Saliva Samples
Hunter Hinton, Lorena Herrera, Sofia Valenzuela, Katherine M. Howard, Karl Kingsley
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Relationship between Expression of P16 and Ki-67 and Persistent Infection of HPV in Cervical Carcinoma Patients
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Analysis of Sequence Variation and Risk Association of Human Papillomavirus 52 Variants Circulating in Korea
Youn Jin Choi, Eun Young Ki, Chuqing Zhang, Wendy C. S. Ho, Sung-Jong Lee, Min Jin Jeong, Paul K. S. Chan, Jong Sup Park, Xuefeng Liu
PLOS ONE.2016; 11(12): e0168178. CrossRef

The Significance of Adhesion Molecules and Granzyme B in Acute Renal Allograft Rejection.: So Yeon Park, Hwal Woong Kim, Hyun Soon Lee; Korean J Pathol. 1999;33(6):404-414.

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Abstract PDF: Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are weakly expressed in normal glomerular cells and vascular endothelial cells, but not in tubules. Granzyme B is a cytotoxic granule present in activated cytotoxic T cells and natural killer cells. To determine the effect of ICAM-1 and VCAM-1 expression and granzyme B-positive cells on histologic grade of rejection, we performed the immunohistochemical study on 19 renal biopsy specimens and one nephrectomy specimen from 14 patients with acute renal allograft rejection using monoclonal antibodies against theses proteins. According to severity of rejection based on Banff classification, three biopsies were classified as borderline, 4 grade I, 12 grade II, and 1 grade III. In all the cases with acute rejection, ICAM-1 and VCAM-1 were expressed in the tubular epithelial cells. The numerical score of ICAM-1 in the tubular epithelial cells was 1.0 in borderline cases, 1.3 0.4 in grade I cases, 2.2 0.8 in grade II cases, and 3.0 in grade III case. The staining intensity of ICAM-1 in the tubular epithelial cells was increased in accordance with histologic rejection grade (P<0.05). The staining intensity of ICAM-1 and VCAM-1 in the renal tubular epithelial cells was increased in accordance with the number of T lymphocytes in the renal parenchyme (r=0.46; P<0.05, r=0.61; P<0.01). The number of granzyme B-positive cells was 6.4 1.6/HPF in borderline cases, 8.1 2.5 in grade I cases, 19.6 11.7 in grade II cases, and 53 in grade III case. The number of T lymphocytes and granzyme B-positive cells was also increased in accordance with histologic rejection grade (P<0.05). These results suggest that ICAM-1 and granzyme B-positive cells may play an important role in the induction of renal allograft rejection and that the grading of severity of these parameters may be useful to predict the prognosis of renal allograft.

Expression of Adhesion Molecules in IgA Nephropathy, Diffuse Crescentic Glomerulonephritis, and Minimal Change Disease.: Kyoung Cheol Moon, So Yeon Park, Hwal Woong Kim, Hyun Soon Lee; Korean J Pathol. 2000;34(5):331-340.

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Abstract PDF: Accumulation of leukocytes within the glomerulus is a key event in the pathogenesis of glomerulonephritis. This process is mediated by pairs of adhesion molecules. We have examined the expression pattern of selectins (E and P), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in 30 renal biopsies with IgA nephropathy, diffuse crescentic glomerulonephritis, and minimal change disease. Normal controls were obtained from four nephrectomy specimens with renal cell carcinoma. ICAM-1 expression was significantly increased in the glomerular endothelial and mesangial cells in cases with IgA nephropathy compared with normal controls. VCAM-1 was expressed in glomerular mesangial cells in all cases with IgA nephropathy and diffuse crescentic glomerulonephritis, but faintly expressed in 3 cases with minimal change disease and not expressed in normal controls. P-selectin was faintly expressed in the glomeruli in cases with IgA nephropathy and diffuse crescentic glomerulonephritis. E-selectin was only expressed in the vascular endothelium in one case with IgA nephropathy and in the other with diffuse crescentic glomerulonephritis. ICAM-1 and VCAM-1 were strongly expressed in the crescents. However, selectin was not expressed in the crescent. These results suggest that adhesion molecules, particularly ICAM-1 and VCAM-1, play an important role in the pathogenesis of glomerular damage and crescent formation in primary glomerular diseases.

Expression of Platelet-Derived Growth Factor and Extracellular Matrix in IgA Nephropathy.: Hwal Woong Kim, Kyoung Cheol Moon, So Yeon Park, Hyun Soon Lee; Korean J Pathol. 2000;34(6):446-455.

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Abstract PDF: Glomerulosclerosis represents a pathological hallmark of progressive glomerular injury. Mesangial cell proliferation and accumulation of extracellular matrix (ECM) proteins in the mesangial area frequently precede the formation of glomerulosclerosis. To understand the role of platelet-derived growth factor (PDGF) and ECM in the development of glomerulosclerosis, we examined the expression of type IV collagen, laminin, fibronectin, and PDGF in 45 renal biopsies diagnosed with IgA nephropathy (IgAN) using a standard peroxidase antiperoxidase (PAP) technique. Normal control specimens were obtained from four nephrectomy specimens diagnosed with renal cell carcinoma. As compared with normal controls, type IV collagen increased in 68%, fibronectin in 73%, laminin in 51%, and PDGF in 36% of patients with IgA nephropathy. The staining intensity of PDGF, type IV collagen, and fibronectin increased significantly in cases with moderate to severe mesangial cell proliferation than cases without. In the areas of glomerulosclerosis, the staining intensity of type IV collagen, laminin, and PDGF decreased, whereas that of fibronectin increased. These results suggest that mesangial cell proliferation in relation to increased PDGF expression in IgAN could stimulate the expression of type IV collagen, laminin and fibronectin leading to mesangial expansion. They also suggest that ECM decreased in advanced glomerulosclerosis. Deposition of fibronectin, which originates mainly from the blood stream, increases during the course of progressive glomerulosclerosis, whereas other ECM components decrease in advanced glomeruloslresosis.

Detection of Helicobacter pylori in the Gastric Mucous Layer in Pediatric Patients.: You Kyung Kim, Jong Sil Lee, Hwal Woong Kim, Jeong Hee Lee, Hee Shang Youn, Gyung Hyuck Ko; Korean J Pathol. 2002;36(5):292-295.

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Abstract PDF: BACKGROUND
Helicobacter pylori is present mainly in the gastric mucous layer. However, the mucous layer, along with the bacteria, is lost during conventional tissue processing in which formalin is used for fixation. The purpose of this study is to ascertain - if the mucous layer is preserved by using Carnoy solution as a fixative - whether the detection rate of H. pylori is increased in pediatric patients.
METHODS
Five pieces of gastric mucosal tissue were obtained from the gastric antrum and the body of one hundred pediatric patients. One of the specimens was fixed with formalin. Another specimen was fixed with Carnoy solution. The tissue sections were stained with hematoxylin-eosin and immunohistochemically stained for H. pylori. For reference, a rapid urease test was performed on the remaining three specimens.
RESULTS
In the formalin-fixed tissue, the detection rate of H. pylori was 13% in the gastric antrum and 12% in the body (overall 16%). In the Carnoy solution-fixed tissue, the mucous layer was preserved and the detection rate of H. pylori was 23% in the antrum and 27% in the body (overall 28%). The positive rate of the rapid urease test was 26% in the antrum and 28% in the body (overall 29%).
CONCLUSIONS
When the number of H. pylori is small in the gastric mucosa, the bacteria may not be detected by conventional histologic methods. In that case, the detection rate of H. pylori may be increased by using Carnoy solution, rather than formalin, as a tissue fixative.

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.

Immunocytochemical Staining for p16 of Atypical Squamous Cells in Cervicovaginal Smear.: Hwal Woong Kim, Jong Sil Lee, Jeong Hee Lee, Gyung Hyuck Ko; Korean J Cytopathol. 2004;15(1):28-32.

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Abstract PDF: It was reported that the main cause of intraepithelial neoplasm and squamous cell carcinoma of the uterine cervix is human papilloma virus infection, and that the expression of p16 is increased in cells infected by human papilloma virus. We performed an immunocytochemical staining for protein p16 in 17 cases of cervocovaginal smears initially diagnosed as atypical squamous cells of undetermined significance, to know whether the staining could help the differentiation of neoplastic cells from reactive atypical cells. Of 17 smears, 6 were diagnosed finally as high grade intraepithelial neoplasm or invasive squamous cell carcinoma by follow-up biopsy and smear, and 5 of the 6 were positive for p16. Three were diagnosed as koilocytosis, and one of them was weakly positive for p16. Eight were diagnosed as reactive atypical cells, and all of them were negative for p16. We thought that immunocytochemical staining of p16 in cervocovaginal smears could help the differentiation of neoplastic cells from reactive atypical cells.

Assessment of Apoptosis by M30 Immunoreactivity and the Relationship with the MSI status and the Clinicopathological Characteristics of Colorectal Carcinomas.: Hyun Jeong Kang, Mee Young Sol, Do Youn Park, Soo Han Lee, Dong Hun Shin, Jee Yeon Kim, Kyung Un Choi, Hwal Woong Kim, Chang Hun Lee, Gi Young Huh; Korean J Pathol. 2006;40(5):319-325.

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Abstract PDF: BACKGROUND
The monoclonal antibody M30 recognizes a neoepitope of cytokeratin 18 that's produced during the process of apoptosis, and it is reactive in formalin-fixed, paraffin-embedded tissue. The detailed nature of apoptosis in colorectal cancer is unclear, especially in regard to the MSI status and the clinicopathologic factors. The purpose of this study was to elucidate the apoptosis assessed by M30 immunoreactivity in colorectal cancer and its relationship with the MSI status and the various clinicopathologic factors of colorectal cancers.
METHODS
101 colorectal cancers were classified according to levels of MSI as 12 MSI-H, 4 MSI-L and 85 MSS. Apoptosis was quantified by immunohistochemistry with using M30 CytoDEATH anti-body.
RESULTS
The apoptotic index assessed by M30 was significantly increased in the MSI-H and MSI-L colorectal cancer compared to that in the MSS colorectal cancer. Right sided colon cancer showed a significant higher apoptotic index than did the left sided colon cancer. There was also a tendency for decreased apoptosis in metastatic colorectal cancers (Duke's stage D). There was somewhat of an increase of apoptosis in colorectal cancers with mucinous carcinoma and medullary carcinoma, and also in the colorectal cancers with an increased TIL count, but this was not statistically significant.
CONCLUSION
M30 immunoreactivity is a valuable method to detect apoptosis in formalin-fixed, paraffin-embedded tissue and it might explain that MSI-H colorectal cancer shows better clinical behavior than MSS colorectal cancer in regard to the increased apoptosis.

Alteration of G1/S Cell Cycle Regulatory Proteins in Ovarian Epithelial Tumors.: Jee Yeon Kim, Hwal Woong Kim, Kyung Un Choi, Chang Hun Lee, Mee Young Sol, Hyun Jeong Kang, Dong Hoon Shin; Korean J Pathol. 2006;40(4):274-281.

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Abstract PDF: BACKGROUND
Disturbances of the cell cycle regulatory proteins are key events underlying the development and/or progression of human malignancies. The aim of this study was to evaluate the expression of G1/S cell cycle regulatory proteins in ovarian epithelial tumor.
METHODS
We simultaneously evaluated the expression of cyclin D1, cyclin E, CDK4, CDK2, p16, Rb, E2F1, p53 and the Ki67 labelling index (LI) by immunohistochemical methods in 148 cases of ovarian epithelial tumor of the benign (n=47), borderline (n=29), and malignant type (n=72).
RESULTS
The expression of cyclin E, CDK2, p16, Rb, E2F1, p53 and the Ki67 LI gradually increased from the benign type, through the borderline type, to the malignant tumors. Between the borderline and malignant tumors, the increased expression of cyclin E, E2F1, and p53, and the decreased expression of Rb were significantly associated with malignancy. The reduced Rb expression and the increased E2F1 expression were correlated with the FIGO stage and the histologic grade in the malignant ovarian epithelial tumors. CONCLUSIONS: Cyclin E, E2F1, and p53 overexpressions and the loss of Rb are the important components during carcinogenesis of ovarian epithelial tumors. Our results suggest that in- creased expression of E2F1 should be considered as a new parameter for the prognosis of patients with malignant ovarian epithelial tumors.

Altered Expression of DNA Topoisomerase IIalpha, Ki-67, p53 and p27 in Non-Hodgkin's Lymphoma.: Kyeong Min Lee, Mee Young Sol, Hyun Jeong Kang, Dong Hoon Shin, Kyung Un Choi, Hwal Woong Kim, Jee Yeon Kim, Do Youn Park, Chang Hun Lee; Korean J Pathol. 2005;39(5):332-337.

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Abstract PDF: BACKGROUND
Topoisomerase II (TOPO II) is an enzyme that separates intertwined chromosomes during DNA synthesis by transiently breaking and joining DNA strands. The level of TOP II is one of the determinants of cellular sensitivity to anti-tumor drugs in non-Hodgkin's lymphoma patients. The alpha form of TOPO II has been recently used as a marker of cellular proliferation. High levels of TOPO IIalpha are expressed in aggressive and proliferative tumors.
METHODS
This study was designed to evaluate the relationship between TOPO IIalpha expression and clinicopathological parameters including age, gender, the serum LDH level, the serum beta2-microglobulin level and stage, or expressions, of Ki-67, p53 and p27, in non-Hodgkin's lymphoma. We analyzed forty-one biopsied tissue specimens from patients with non-Hodgkin's lymphoma.
RESULTS
The expression of TOPO IIalpha increased with the clinical stage and it was correlated with Ki-67 and p53 expressions. However, TOPO IIalpha expression did not have any significant correlation with age, gender, the serum LDH level, the serum 2-microglobulin level and the p27 expression.
CONCLUSIONS
TOPO IIalpha expression is a useful marker of cellular proliferation and it may serve as a prognostic factor of a tumor's progression and aggressiveness in non-Hodgkin's lymphomas.

Studies on the Expression of the p16 (INK4A), p53, and Ki-67 Labeling Index in Inflammatory and Neoplastic Diseases of the Uterine Cervix.: Jong Sil Lee, Jeong Gyu Shin, Gyung Hyuck Ko, Jeong Hee Lee, Hwal Woong Kim; Korean J Pathol. 2004;38(4):238-243.

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Abstract PDF: BACKGROUND
Prior studies of p16, p53, and Ki-67 expression have suggested that these markers may be preferentially expressed in cervical neoplasms. The purpose of this study was to assess the expression and clinical significance of p16, p53 proteins, and the Ki-67 labeling index in the cervical lesions.
METHODS
We analyzed 54 uterine cervical specimens obtained by surgical biopsy. The expression of p16, p53 proteins, and Ki-67 was evaluated by immunohistochemical methods. The immunohistochemical findings were then correlated with the histologic diagnosis.
RESULTS
Positive scores for p16, p53, and Ki-67 were seen in 75% (6/8), 0% (0/8), and 13% (1/8) of low grade intraepithelial lesions (LSIL), respectively, and 100% (23/23), 17% (4/23), and 74% (17/23) of high grade intraepithelial lesions (HSIL), respectively, and 100% (10/10), 20% (2/10), and 70% (7/10) of invasive squamous cell carcinomas, respectively. Both normal epithelium and inflammatory lesions scored negative for these three markers in all of the 13 cases. p16 and Ki-67 expression correlated with the severity of uterine cervix lesions.
CONCLUSIONS
p16 and Ki-67 are complementary surrogate biomarkers for cervical squamous intraepithelial neoplasia. However, immunohistochemical expression for p53 has no correlation with the grade of cervical squamous intraepithelial neoplasia.

Case Reports

Solitary Fibrous Tumor of the Urinary Bladder: A Case Report.: Jong Sil Lee, Jeong Seok Hwa, Gyung Hyuck Ko, Jeong Hee Lee, Hwal Woong Kim; Korean J Pathol. 2004;38(2):129-131.

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Abstract PDF: Solitary fibrous tumor (SFT) most commonly affects the pleura and these tumors have been recently reported to be found in unusual locations. We describe here a solitary fibrous tumor of the urinary bladder that was removed from a 79-year-old man having a history of gross hematuria and dysuria. Transabdominal ultrasonography showed a huge soft tissue mass in the urinary bladder. The cut surface of the tumor showed a grayish-white, hemorrhagic and gelatinous appearance. Necrosis was not found. Microscopically, the tumor showed a proliferation of spindle or ovoid cells that were intervened by a collagenous stroma. A variety of growth patterns was identified but the so-called patternless pattern was the predominant one. The spindle cells had almost no mitotic figures, and there was very little or no nuclear atypia. Immunohistochemical stains showed a strong reactivity for CD34 and a focal reactivity for bcl-2. The ultrastructure of the tumor cells showed mesenchymal-myofibroblastic traits.

Sinonasal Undifferentiated Carcinoma: A Case Report.: Hwal Woong Kim, Gyung Hyuck Ko, Chul Woo Kim; Korean J Pathol. 2003;37(3):214-217.

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Abstract PDF: Sinonasal undifferentiated carcinoma (SNUC) is a rare, aggressive neoplasm arising in the nasal cavity and paranasal sinuses. We report a case of SNUC in an old woman. The tumor was located at the nasal cavity and ethmoid sinus, extending to the cranial cavity. The nasopharynx was free from the tumor. Microscopically, the tumor formed nests or sheets containing medium-sized cells with small amounts of eosinophilic cytoplasm. High mitotic rates and tumor necrosis were characteristic. There was no evidence of glandular or squamous differentiation. The tumor was focally weak positive for cytokeratin, but negative for vimentin, leukocyte common antigen, S-100 protein, chromogranin, synaptophysin and neuron specific enolase. Epstein Barr Virus EBER-1 was not detected by in situ hybridization. SNUC is a highly aggressive tumor and must be distinguished from less aggressive sinonasal neoplasms.

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