Journal of Pathology and Translational Medicine

Original Articles

The Expression of Pigment Epithelium-Derived Factor in Bladder Transitional Cell Carcinoma: Tae Jung Jang, Sung Woo Kim, Kyung Seop Lee; Korean J Pathol. 2012;46(3):261-265. Published online June 22, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.3.261

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Background

Pigment epithelium-derived factor (PEDF) is an anti-angiogenic factor. The purpose of this study is to examine the involvement of PEDF in the angiogenesis and biological behavior of bladder transitional cell carcinoma (TCC).

Methods

We examined the expression of PEDF in 99 bladder TCCs and ten non-neoplastic tissues, and evaluated microvessel density (MVD).

Results

The positive immunoreactivity for PEDF was seen in normal urothelium in 60% (6/10) and TCC in 13% (13/99). The PEDF expression had a significant correlation with MVD, i.e., a low MVD in 42% (5/12), a middle MVD in 11% (8/76) and a high MVD 0% (0/11) of tumors. The PEDF expression was not significantly correlated with the differentiation and invasion of TCC, but the degree of MVD was significantly higher in both high grade TCC and the pT2 tumors.

Conclusions

The degree of PEDF expression is significantly higher in normal bladder urothelium than bladder TCC; it is inversely correlated with the angiogenesis; and it is not related to the differentiation and progression of TCC. It can therefore be concluded that bladder TCC would initially occur if there is a lack of the PEDF expression.

Citations

Citations to this article as recorded by

Association of pigment epithelium derived factor expression with cancer progression and prognosis: a meta-analysis study
Guo Cheng, Crystal Song
Discover Oncology.2021;[Epub] CrossRef
Level of mitoses in non-muscle invasive papillary urothelial carcinomas (pTa and pT1) at initial bladder biopsy is a simple and powerful predictor of clinical outcome: a multi-center study in South Korea
Ji Eun Kwon, Nam Hoon Cho, Yeong-Jin Choi, So Dug Lim, Yong Mee Cho, Sun Young Jun, Sanghui Park, Young A. Kim, Sung-Sun Kim, Mi Sun Choe, Jung-dong Lee, Dae Yong Kang, Jae Y. Ro, Hyun-Jung Kim
Diagnostic Pathology.2017;[Epub] CrossRef
Endogenous Gastric-Resident Mesenchymal Stem Cells Contribute to Formation of Cancer Stroma and Progression of Gastric Cancer
Eun-Kyung Kim, Hye-Jung Kim, Young-Il Yang, Jong Tae Kim, Min-Young Choi, Chang Soo Choi, Kwang-Hee Kim, Jeong-Han Lee, Won-Hee Jang, Soon-Ho Cheong
Korean Journal of Pathology.2013; 47(6): 507. CrossRef

Immunohistochemical Study for p53 and hsc70 in Transitional Cell Carcinoma of the Urinary Bladder: Correlation with Histologic Grade, Clinical Stage and DNA Ploidy Pattern.: Hyuni Cho, Sung Jin Cho, Han Kyeom Kim, Yang Seok Chae; Korean J Pathol. 1995;29(6):766-775.

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Abstract PDF: Transitional cell carcinoma of the urinary bladder is the most common cancer of the genitourinary tract in Korea and its prognosis is determined by the histologic grade and clinical stage present at initial diagnosis. Recently, an extensive search for a more objective and reproducible method to evaluate the proliferation activity of cancer cells has been done. The p53 gene is located on the short arm of the chromosome 17 and acts as a cancer suppressor gene. Mutant p53 gene induces malignant transformation. Recent studies reveal that the level of mutant p53 protein is elevated in some human tumor and many diverse transformed cell lines. Heat shock proteins(HSPs) are present constitutively in normal cells, where they play an important role in normal cell metabolism. In mammalian cells, they are induced by a variety of physical and chemical stimuli. A protein that belongs to the hsp70 family, called hsc70, is only slightly heat inducible and is found at a higher level in growing cells than in the resting cells. The mutant p53 protein binds with hsc70 and the p53-hsc70 complex has functional significance in the transforming capacity of the mutant p53. We investigated the correlation between the p53 and hsc70 by immunohistochemical methods and with better defined prognostic indicators such as histologic grade, clinical stage, and DNA ploidy pattern in 42 transitional cell carcinomas of the urinary bladder. The results are summarized as follows. p53 expression rate was higher in the DNA aneuploid group than in the DNA diploid group(p=0.061), but there was no significant difference in the histologic grade(p=0.861) or clinical stage(p=0.154). The higher the hsc70 expression rate was, the poorer the tumor differentiation(p=0.000) and the deeper the invasion(p=0.001). The aneuploid group showed a higher hsc70 expression rate than the diploid group(p=0.017). 27 of 42(64.3%) carcinomas showed positivity of both p53 and hsc70. Though statistically insignificant, their correlation showed a relatively low correlation coefficient (P=0.059). In conclusion, we suspect that p53 and hsc70 are closely correlated to each other by comparing the results of this immunohistochemical study, and hsc70 will be a useful prognostic marker in transitional cell carcinomas of the urinary bladder after sufficient follow up studies are performed.

Correlation between Histopathologic Grade, Stage, and Degree of EGFR Expression in Transitional Cell Carcinoma of the Urinary Bladder.: Hyeon Ok Kim, Hwa Sun Lee, Kang Suek Suh; Korean J Pathol. 1996;30(9):784-791.

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Abstract PDF: This study was performed to estimate the correlation between the histopathological grade and the clinical stage, which are known as important prognostic factors, and EGFR expression status in 57 cases of transitional cell carcinoma of the urinary bladder. There was a significant correlation between the histopathological grade and clinical stage of transitional cell carcinoma of the urinary bladder and between expression grades of EGFR and histopathological grades, or clinical stages of transitional cell carcinoma of the urinary bladder. Therefore, the presence of a high intensity of EGFR staining in the transitional cell carcinoma of the urinary bladder was associated with poor differentiation and invasion. On the basis of the above results, it was suggested that the degree of EGFR expression is one of the objective and reliable prognostic factors in transitional cell carcinoma of the urinary bladder.

Expressions of Epidermal Growth Factor Receptor, c-erbB-2 and p53 Protein as Useful Markers of Malignant Potential in a Transitional Cell Carcinoma of the Urinary Bladder.: Gu Kong, Ki Yong Shin, Sun Jin Kim, Young Hyeh Ko, Hae Young Park, Young Nam Woo, Jung Dal Lee; Korean J Pathol. 1997;31(1):51-58.

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Abstract PDF: Transitional cell carcinoma(TCC) of the urinary bladder shows marked heterogeneity in biological behaviors. Evidence has accumulated that biological markers may provide significant information to predict the potential aggressiveness of TCC. We have assessed the expression of the epidermal growth factor receptor (EGF-R), c-erbB-2 and p53 proteins in 56 cases of TCC to investigate the prognostic significance of differential expression of these oncoproteins using an immunohistochemical method. We analysed the expression patterns of these oncoproteins according to tumor stage and grade. And we assessed the probability of progression-free survival in stage T1 tumors according to their expressions. Positive rates of EGF-R (>+3 staining intensity), c-erbB-2 (intense membrane staining) and p53 proteins (>20% positive cells) were 73.2%, 37.5% and 42.9%, respectively. Invasive tumors had significantly higher positive rates of all three factors than did superficial tumors (p<0.005 for EGF-R and c-erbB-2, p<0.05 for p53). High grade tumors had significantly higher positive rates of c-erbB-2 and p53 proteins (p<0.005). In superficial tumors, T1 tumors had higher positive rate of p53 protein compared with Ta tumors (p<0.05). Twelve cases of superficial tumors (34.3%) were positive for EGF-R and negative for c-erbB-2 and p53 proteins. Nine cases of superficial tumors(25.7%) were negative for all three factors. In invasive tumors, however, 42.5% of the cases were positive for all three factors. The overexpression of p53 protein was the only useful marker to predict the rapid progression in stage T1 tumors (p<0.05, log-rank test). These results suggest that the differential overexpression of EGF-R, c-erbB-2 and p53 proteins could be useful to depict tumor aggressiveness of TCC of the urinary bladder. And, the overexpression of a p53 protein may be a useful marker to predict the possibility of rapid progression in stage T1 tumors.

Prognostic Significance of PCNA Index and AgNORs Score in Transitional Cell Carcinoma of the Renal Pelvis.: Wan Seop Kim, Seung Sam Paik, Nam Hoon Kim, Moon Hyang Park, Jung Dal Lee; Korean J Pathol. 1998;32(7):521-530.

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Abstract: Proliferative activity of a malignant tumor is known to reflect its biological aggressiveness. Proliferating cell nuclear antigen (PCNA) is a marker of cellular proliferation, and silver-stained nucleolar organizer regions (AgNORs) have been shown to correlate with ploidy and proliferative activity of cells. In transitional cell carcinoma of the renal pelvis, the prognostic value of these markers has not been well defined. We studied PCNA expression and the AgNORs count in 22 transitional cell carcinoma of the renal pelvis to assess their prognostic significance compared with their cumulative survival rate, the stage of disease and histopathologic features of the tumors. An immunohistochemical method and a standard colloidal silver staining were used. The mean percentage of PCNA positivity (PCNA index) and the mean number of AgNORs per nucleus (AgNORs score) were determined. In a multivariable analysis, PCNA indexes were significantly associated with tumor stage (p=0.024), whereas AgNORs scores were not significantly associated with the stage or histopatholgic features of the tumors. Histologic grade was correlated to disease stage at a significant level (p=0.000). But there was a trend of low tumor PCNA-indices or AgNORs counts with survival advantage for patients, but this did not reach statistical significance. The results suggest that the fraction of PCNA positive nuclei would be useful for investigating the malignant potential of renal pelvic cancers, although their clinical use as markers of biologic behavior may be limited.

Case Report

Sarcomatoid Transitional Cell Carcinoma of the Renal Pelvis A report of two cases.: Kyo Young Lee, Mi seon Kwon, Yeong Jin Choi, Chang Suk Kang, Seok Jin Kang, Baying Kee Kim, Sang In Shim; Korean J Pathol. 1999;33(2):128-132.

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Abstract: Sarcomatoid carcinomas are malignant epithelial neoplasms in which the tumor cells assume a partial or complete spindle cell pattern of growth, leading to the erroneous classification of some true carcinomas as sarcomas. These spindle cells are malignant and manifest various amount of both vimentin and cytokeratin. Positive reaction of some of the spindle cells for cytokeratin antibodies is confirmatory. Clinical features do not differ significantly from those of patients with high-grade transitional cell carcinoma. So far, 13 cases of sarcomatoid transitional cell carcinoma of the renal pelvis have been reported in English and Korean literature. In this report, we describe clinicopathologic features of recently observed two cases of sarcomatoid transitional cell carcinoma of the renal pelvis and summarize the pathologic findings of previously reported cases with review of the literature.

Original Articles

Expression of p27Kip1 Protein in Carcinoma of the Urinary Bladder.: Ki Kwon Kim, Jung Ran Kim; Korean J Pathol. 2000;34(5):341-348.

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Abstract PDF: The cyclin-dependent kinase (cdk) inhibitor p27Kip1 gene is a powerful molecular determinant of cell cycle progression. Loss of expression of p27Kip1 has recently been shown to be predictive of disease progression in several human malignancies. The prognostic value and expression of p27Kip1 have been incompletely studied in bladder cancer. In this study, we investigated the relationship between p27Kip1 protein expression and clinicopathologic parameters in 50 cases of carcinoma of the urinary bladder by conducting immunohistochemical analysis and DNA flow-cytometry. Malignant bladder tissue demonstrated a heterogeneous pattern of p27Kip1 immunoreactivity. In addition, there was progressive loss of expression with increasing tumor grade. The expression of p27Kip1 protein was unrelated to stage, DNA ploidy and S phase fraction (SPF). SPF was unrelated with tumor grade and DNA ploidy. The results indicate that p27Kip1 is frequently expressed in well differentiated transitional cell carcinomas of the urinary bladder but less often expressed in muscle-invasive transitional cell carcinomas. The expression of p27Kip1 and its prevalence in low-grade tumors may reflect growth regulatory influences and potential inhibiting action in tumor progression and novel predictive markers of the biological potential of bladder tumors.

Expression of c-erbB-2, c-myc, c-fos, bcl-2, p53, PCNA, and TGF-alpha in Transitional Cell Carcinoma of the Urinary Bladder.: Keun Hong Kee, Yoon Kyeong Oh; Korean J Pathol. 2000;34(7):516-523.

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Abstract PDF: Most of malignant tumors in the urinary bladder is transitional cell carcinoma (TCC) deriving from the urothelium. Clinical stage and histopathologic grading of the TCC of the urinary bladder is important in the determination of the patient's prognosis. To investigate the correlation between the prognostic factors and the expression of the various oncoproteins and growth factors in each grade of the TCC, immunohistochemical stains for c-erbB2, c-myc, c-fos, bcl-2, p53, proliferating cell nuclear antigen (PCNA), and transforming growth factor-alpha (TGF-alpha) were performed in the formalin fixed paraffin embedded tissues of the TCC (Grade I; 15 cases, Grade II; 20 cases, Grade III; 15 cases) of the urinary bladder. The immunoexpression rate of c-erbB2 was immunoexpression 78.0% in the grade I, 85.0% in the grade II, and 95.0% in the grade III TCC. The immunoexpression rate of c-myc, c-fos and bcl-2 was below 5% in each grades of TCC. The p53 immunoexpression was identified in 11.5%, 24.3% and 30.6% of the grade I, II, and III TCC, respectively. The PCNA and TGF-alpha expression was 53.0% and 27.6% in the grade I, 77.3% and 32.7% in the grade II, and 78.2% and 37.3% in the grade III TCC, respectively. These results suggest that the expressions of c-myc, c-fos, bcl-2, and TGF-alpha are similar in each grade of the TCC and the positivity of c-erbB2, p53, and PCNA shows an increasing tendency for the higher grade TCC of the urinary bladder. Therefore, c-erbB2, p53, and PCNA are clinically useful predictors of the patient's prognosis.

Expression of bcl-2 and p53 Protein, and Apoptosis in Transitional Cell Carcinoma of the Bladder.: Myoung Ja Chung, Sang Su Kim, Ho Yeul Choi; Korean J Pathol. 2000;34(8):567-573.

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Abstract PDF: This study examined the expression of the bcl-2 protein in 59 cases of transitional cell carcinomas (TCCs) of the bladder and evaluated the relationship of bcl-2 and p53 with apoptosis. The cases were divided into 41 low-grade TCCs, 18 high-grade TCCs, 32 superficial TCCs, and 27 invasive TCCs. p53 and bcl-2 protein were detected by the immunohistochemical method and apoptosis was analysed by using hematoxylin-eosin stained slide. The results were as follows: bcl-2 protein was detected in 8 (14%) TCCs and all of these cases were low grade TCCs. Expression of bcl-2 protein was not correlated with clinical stage. There was no correlation between bcl-2 and p53 protein. According to the immunohistochemical results of bcl-2 and p53 protein, the cases were divided 4 groups. Apoptotic index (AI) was higher in p53 positive/ bcl-2 negative group than other groups but the significance was recognized only between p53 positive/bcl-2 negative group and p53 negative/bcl-2 negative group (p<0.05). p53 protein was detected in 20 (36%) TCCs and its expression was correlated positively with histologic grade and clinical stage (p<0.05). AI correlated positively with histologic grade and clinical stage (p<0.01). These data indicate that overexpression of bcl-2 protein is rare in TCC of the bladder and associated with low grade TCCs. Overexpression of p53 is associated with the tumor progression in the TCCs. AI correlates with p53 positivity but does not correlate with bcl-2 positivity.

Cyclin D1 Protein Expression is Inversely Correlated with p53 Protein in Primary and Recurrent Transitional Cell Carcinoma of the Urinary Bladder.: Min Jin Lee, Sun Hee Sung, Woon Sup Han; Korean J Pathol. 2000;34(12):1009-1015.

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Abstract PDF: Transitional cell carcinoma of the urinary bladder is the most common cancer of the urinary tract and is characterized by frequent recurrence. Like the other malignant tumor, the genetic alterations leading to neoplastic transformation of the urothelium are related with the activation of oncogenes and loss of functional tumor suppressor genes. Cyclin D1 is a putative protooncogene as cell cycle regulator essential for G1 phase progression and is frequently overexpressed in several human tumor. In this study we performed immunohistochemical stainings of cyclin D1 and p53 in both primary and recurrent transitional cell carcinomas of urinary bladder from 56 patients including 20 cases of recurrent tumor, and compared their results with histopathologic features. The results were as follows. Cyclin D1 immunoreactivity was found in 10 of 10 cases (100%) of grade 1, 25 of 41 (61%) cases of grade 2, and 11 of 25 (44%) cases of grade 3 transitional cell carcinomas. p53 immunoreactivity was found in 40% of grade 1, 63% of grade 2, and 87% of grade 3 lesions. Cyclin D1 expression was significantly higher in Ta and T1 lesions than T2 to T4 by pathologic tumor stage. Conversely p53 immunoreactivity was increased in proportion to the T classification. Cyclin D1 was de creased in recurrent transitional cell carcinomas, compared with primary transitional cell carcinomas. However, there was no statistical significance. In conclusion, cyclin D1 immunoreactivity is associated with low histologic grade and low tumor stage. And there is inverse relationship between the cyclin D1 and p53 overexpression.

Urinary Cytologic Findings of Transitional Cell Carcinoma: Analysis of 83 Cases.: Yeon Mee Kim, Hye Je Cho; Korean J Cytopathol. 1995;6(2):148-155.

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Abstract PDF: Urinary cytology has become an essential element in the diagnosis and management of transitional cell carcinoma(TCC) of the urinary tract. It has the advantage of being noninvasive, inexpensive, and easily accessible. Besides that it can even detect malignancy when unsuspected at cystoscopy. We report a retrospective review of urine cytology in the diagnosis of 83 TCC cases that underwent 295 cytologic evaluation. All patients had biopsy-proven TCC of the bladder, ureter and renal pelvis. The overall incidence of the positive cytology cases was 66.2%. To define the cytologic features of tumor cells, we tried to use three cytologic gradings such as "grade 1", "grade 2", and "grade 3" according to the cytologic degree of anaplastic neoplastic cells. These cytologic gades of TCC were relatively well correlated with the histologic grade and tumor invasiveness. This result suggests that the recognition of characteristic cellular features of TCC can suspect the histologic grade and tumor stage. The false negative TCC cases were 78.9%. They showed severe inflammatory or bloody background and a few neoplastic cells. Therefore, a cautious approach for accurate interpretation, personal experience, and proper fixation and processing could expand the role of urinary cytology.

Case Reports

Urinary Cytologic Findings of Plasmacytoid Transitional Cell Carcinoma of the Urinary Bladder: A Case Report .: Mi Ok Park, Yong Jin Kim, Jae Bok Park; Korean J Cytopathol. 1999;10(1):67-71.

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Abstract PDF: We report a case of 53-year-old man with plasmacytoid transitional cell carcinoma of the urinary bladder, which may be confused with plasmacytoma. The patient initially presented with gross hematuria and dysuria for two months. Cystoscopy and radiologic studies revealed multiple intraluminal protruding masses on the urinary bladder invading perivesical fat tissue. After urinary cytologic examination and cystoscopic biopsy, radical cystectomy and pelvic lymph node dissections were done. Urine cytology showed single cells and poorly cohesive cells with round eccentric nuclei, bi-or multi-nucleation, indistinct nucleoli, coarse chromatin, and abundant basophilic cytoplasm within relatively clear background. The cytologic findings of tumor cells were similar to the plasma cells seen in plasmacytoma. The tumor of the bladder was composed of discohesive, individual cancer cells with diffuse pattern that simulated lymphoma or plasmacytoma. Immunohistochemical and electron microscopic studies clearly established the epithelial nature of the neoplasm. Recognition of this plasmacytoid type of transitional cell carcinoma of the urinary bladder can avoid the misdiagnosis.

Urinary Cytologic Findings of Small Cell Neuroendocrine Carcinoma: A Case Report.: Dong Hoon Kim, Dong Wook Kang, Kyung Hee Kim, Ju Heon Kim, Mee Ja Park; Korean J Cytopathol. 2002;13(2):78-83.

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Abstract PDF: We report the cytologic features of a case of primary small cell carcinoma of the urinary bladder with high grade transitional cell and signet ring cell carcinomatous components. A 64-year-old male presented with gross hematuria for one week. Computed tomography revealed an ill-defined mass in the left lateral wall of the urinary bladder. Urinary cytology showed hypercellularity with predominantly isolated single cells and clustered cells. They have scanty cytoplasm and naked hyperchromatic nuclei with finely granular nuclear chromatin and rare nucleoli. The tumor cells occurred predominantly singe cells, but a few in clusters. Nuclear molding was prominent. No glandular formation or nesting was noted. The second tumor cells had high nuclear/cytoplasmic ratio, irregular nuclear membrane, and coarse granular chromatin. The background was inflamed and necrotic. The histologic findings of transurethral resection were mainly composed of small cell carcinoma, and partly transitional cell and signet ring cell carcinomatous components. Small cell neuroendocrine carcinoma have distinctive cytologic features to make a proper diagnosis.

A Sertoli-Leydig Cell Tumor in a Patient with Complete Androgen Insensitivity Syndrome: A Case Report.: Min Sung Choi, Dong Won Kim, So Young Jin, Sang Mo Park, Dong Wha Lee; Korean J Pathol. 2007;41(1):59-62.

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Abstract PDF: Complete androgen insensitivity syndrome (CAIS) is a rare disorder sometimes referred to as male pseudohermaphroditism. This syndrome is characterized by a 46,XY karyotype with internal bilateral testes, female external genitalia, absence or scantiness of pubic and axillary hair and normal breast development. A variety of gonadal tumors can develop in individuals with CAIS. A 57-year-old patient was admitted to urology with intermittent gross hematuria for one month. CT revealed a left ureteric mass, measuring 2.5 x 2 cm. Ureteroscopic biopsy was performed and the result was a diagnosis of high grade urothelial carcinoma. The patient underwent laparotomy which revealed slightly enlarged gonads in the pelvic cavity. However, a uterus and fallopian tubes were not identified. Left nephroureterectomy and bilateral gonadectomy were performed. The right gonad measured 3.9 x 2.5 x 2 cm and the cut surface showed a well circumscribed, firm, brownish gray colored 2 x 1.8 cm sized nodule. Microscopically, this nodule consisted of uniform and solid tubules containing immature Sertoli cells and Leydig cells which were both positive for alpha-inhibin. The left gonad measured 3.5 x 2 x 1.9 cm and showed atrophic testicular tissue.

ISUP/WHO Classification of Papillary Urothelial Neoplasms of Urinary Bladder: Consensus Study Conducted by Korean Society of Urogenital Pathology.: Jung Weon Shim, Jae Y Ro, Nam Hoon Cho, Young Sik Kim, Yong Wook Park, Sang In Shim, Dong Wha Lee, Yeong Jin Choi, Woon Sup Han; Korean J Pathol. 2006;40(4):282-288.

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Abstract PDF: BACKGROUND
Pathologic grading, one of the most important prognostic factors of papillary urothelial neoplasia (PUN) of the urinary bladder, has been revised continuously. The current study focused on the analysis of interobserver agreement on PUN of the urinary bladder bet- ween 1973 WHO classification (WHO 1973) and 1998 WHO/ISUP classification.
METHODS
Seventy five cases from 15 institutions were collected, and after review by Korean Society of Urogenital Pathology (KSUP), 30 cases were selected as follows; group I, WHO grade 1 and papillary urothelial neoplasm of low malignant potential by ISUP (7 cases), group II, WHO grade 2 and low-grade papillary urothelial carcinoma (16 cases), and group III, WHO grade 3 and high-grade papillary urothelial carcinoma (7 cases). Seventy five general surgical pathologists who participated in this study were asked to grade the tumors based on WHO/ISUP classification. Interobserver agreement between the participants' diagnosis and KSUP consensus diagnosis was analyzed by kappa value.
RESULTS
Interobserver agreement assessed by kappa value for all diagnostic groups was very low; for group I, kappa value was -0.900893722; for group II, -0.944650025, and for group III, -0.876728996. The overall kappa value of pathology residents was better than that of practicing pathologists.
CONCLUSIONS
The 1998 WHO/ ISUP classification could not be easily translated from the 1973 WHO classification and because of poor interobserver agreement, it appears that further work would be needed before it can be practically applied.

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