Journal of Pathology and Translational Medicine

Original Articles

Do Helper T Cell Subtypes in Lymphocytic Thyroiditis Play a Role in the Antitumor Effect?: Seok Woo Yang, Seong-Ho Kang, Kyung Rae Kim, In Hong Choi, Hang Seok Chang, Young Lyun Oh, Soon Won Hong; J Pathol Transl Med. 2016;50(5):377-384. Published online September 15, 2016; DOI: https://doi.org/10.4132/jptm.2016.07.25

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Background
Papillary thyroid carcinoma (PTC) is frequently accompanied by lymphocytic thyroiditis (LT). Some reports claim that Hashimoto’s thyroiditis (the clinical form of LT) enhances the likelihood of PTC; however, others suggest that LT has antitumor activity. This study was aimed to find out the relationship between the patterns of helper T cell (Th) cytokines in thyroid tissue of PTC with or without LT and the clinicopathological manifestation of PTC.
Methods
Fresh surgical samples of PTC with (13 cases) or without (10 cases) LT were used. The prognostic parameters (tumor size, extra-thyroidal extension of PTC, and lymph node metastasis) were analyzed. The mRNA levels of two subtypes of Th cytokines, Th1 (tumor necrosis factor α [TNF-α], interferon γ [IFN-γ ], and interleukin [IL] 2) and Th2 (IL-4 and IL-10), were analyzed. Because most PTC cases were microcarcinomas and recent cases without clinical follow-up, negative or faint p27 immunoreactivity was used as a surrogate marker for lymph node metastasis.
Results
PTC with LT cases showed significantly higher expression of TNF-α (p = .043), IFN-γ (p < .010), IL-4 (p = .015) than those without LT cases. Although the data were not statistically significant, all analyzed cytokines (except for IL-4) were highly expressed in the cases with higher expression of p27 surrogate marker.
Conclusions
These results indicate that mixed Th1 (TNF-α, IFN-γ , and IL-2) and Th2 (IL-10) immunity might play a role in the antitumor effect in terms of lymph node metastasis.

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Obesity and Thyroid Cancer Risk: An Update
Fabiana Franchini, Giuseppe Palatucci, Annamaria Colao, Paola Ungaro, Paolo Emidio Macchia, Immacolata Cristina Nettore
International Journal of Environmental Research and Public Health.2022; 19(3): 1116. CrossRef
Association between Hashimoto thyroiditis and clinical outcomes of papillary thyroid carcinoma: A meta-analysis
Qizhi Tang, Weiyu Pan, Liangyue Peng, Francis Moore
PLOS ONE.2022; 17(6): e0269995. CrossRef
The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines
Peter Chin Wan Fung, Regina Kit Chee Kong
Journal of Cancer Therapy.2017; 08(11): 962. CrossRef

Significance of the Expression of Cyclin-Dependent Kinase Inhibitor, p27Kip1, in Human Breast Cancer.: Sang Yong Song, Duck Hwan Kim, Yeon Lim Suh, Young Hyeh Ko, Dae Shick Kim, Seok Jin Nam, Jung Hyun Yang; Korean J Pathol. 1998;32(12):1081-1088.

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Abstract: p27Kip1 protein, a negative cell cycle regulator in G1 progression, has been reported to be related with human cancers including colon, breast and non-small cell lung carcinomas. To elucidate a possible prognostic indicator, we studied 49 cases of human breast carcinoma for expression of p27Kip1 protein using an immunohistochemical method, and compared these results with known prognostic parameters of the breast cancer. p27Kip1 protein was intensely stained in nuclei of carcinoma cells in 26 cases (53.1%). The expression rate of p27Kip1 protein was significantly higher in higher nuclear grade (p<0.05), lower histologic grade (p<0.01), lower N classification (p<0.001) and lower clinical stage (p<0.05) than in lower nuclear grade, higher histologic grade, higher N classification and higher clinical stage, respectively. p27Kip1 protein expression was significantly correlated with progesterone receptor status (p<0.05) or cyclin D expression (p<0.05). No statistical correlations were found between expression of p27Kip1 protein and other parameters including tumor size, estrogen receptor status, p53 overexpression and c-erbB-2 expression. The results suggest that reduced expression of p27Kip1 protein plays a role in biologically aggressive behavior of breast carcinoma and might contribute in predicting breast cancer patient's survival.

Expression of p27kip1, Cyclin D1 and p53 Protein in Ductal Carcinoma In Situ of the Breast.: Young Lyun Oh, Sang Yong Song, Jong Sun Choi, Young Hyeh Ko, Hwoe J Ree, Geung Hwan Ahn; Korean J Pathol. 1999;33(9):709-716.

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Abstract PDF: p27(kip1) protein, a cyclin-dependent kinase inhibitor, has been reported to be a powerful negative prognostic marker in patients with breast carcinoma. However, to this day, studies on p27(kip1) protein expression in ductal carcinoma in situ (DCIS) have been extremely limited. We studied the immunohistochemical expression of p27(kip1) protein in 49 cases of the DCIS and compared the findings to the clinicopathologic parameters, cyclin D1, p53 and estrogen receptor (ER). Positive nuclear staining of p27(kip1) protein was identified in 23 (46.9%) cases. The p27(kip1) protein expression correlated positively with the cyclin D1 immunopositivity (p<0.005) and ER expression (p<0.005). No significant associations were seen in the p27(kip1) protein expression and clinicopathologic parameters. The overexpression of cyclin D1 (59.2% of the cases) correlated positively with ER expression (p<0.001). The p53 protein expression was identified in 30.6% and seemed to be correlated inversely with ER expression (p=0.06). The DCISs with high grade nuclei were more likely to be p53-positive (p<0.05). Our data suggest that the expression of p27(kip1) protein as well as cyclin D1 and p53 protein may be influenced by the ER status in DCIS. The significantly positive correlation of p27(kip1) protein and cyclin D1 expression (p<0.005) supports the theory that the balance of the two opposing signals is important in determining the cell proliferation in breast cancers. Therefore, a comprehensive understanding of loop reaction of p27(kip1)-cyclin D1-ER may be necessary for the treatment of DCIS.

p27Kip1 Expression and Apoptotic Index in Prostatic Adenocarcinoma.: Eun Sook Nam, Duck Hwan Kim, Hyung Sik Shin, Young Euy Park, Dae Yul Yang; Korean J Pathol. 1999;33(12):1139-1145.

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Abstract PDF: p27kip1, a cyclin dependent kinase inhibitor, has been recognized as a negative regulator of cell cycle. To investigate the role of p27kip1 on progression of cancer and apoptotic pathway, we analyzed p27kip1 expression using immunohistochemical stain in 40 cases of prostatic adenocarcinoma and apoptotic index by TUNEL method in 30 cases of prostatic adenocarinoma. Both were correlated with Gleason grade and Gleason score. Loss of p27kip1 expression was more frequent in prostatic adenocarcinomas of higher score (Gleason score 7 to 10) (60.7%) than in those of lower score (Gleason score 4 to 6) (33.3%) (p<0.05). The value of mean apoptotic index of carcinoma was 1.13+/-0.26, 1.80+/-0.91, 2.06+/-0.79, and 2.12+/-0.82 in grade 2, 3, 4, and 5, respectively, and was positively correlated with grade of carcinoma (p<0.05). Mean apoptotic index of higher Gleason score (score 7 to 10; 2.05+/-0.63) was also significantly increased than in lower Gleason score (score 4 to 6; 1.34+/-0.39) (p<0.05). Mean apoptotic index in cases with and without p27kip1 expression was 1.92+/-0.86 and 1.89+/-0.81, respectively (p>0.05). These results suggest that loss of p27kip1 expression and increased apoptotic index may be the morphologic markers to predict the behavior of prostatic adenocaricnoma. The role of p27kip1 on apoptotic pathway seems to be meager in this study and needs further study.

Expression of p27Kip1 Protein in Colorectal Adenocarcinoma.: Hyang Im Lee, Duck Hwan Kim, Eun Sook Nam, Hye Rim Park, Seoung Wan Chae, Chul Jae Park, Jeong Rye Kim, Hyung Sik Shin; Korean J Pathol. 2000;34(2):132-137.

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Abstract PDF: p27Kip1 has been recognized as a negative regulator of cell cycle. Reduced level of p27 expression is associated with development and aggressiveness of several human tumors. To investigate the role of p27Kip1 on progression of colorectal adenocarcinoma, we studied 40 cases of human colorectal adenocarcinomas for expression of p27Kip1 protein using an immunohistochemical method, and compared these results with known prognostic parameters of colorectal adenocarcinoma. Among 40 cases of colorectal adenocarcinomas, p27Kip1 expression was detected in the nuclei of tumor cells in 14 cases (35%). The expression rate of p27Kip1 protein was significantly lower in the cases with lymph node metastasis (25.8%) than in those without lymph node metastasis (66.6%) (p<0.05). But it did not correlate with other parameters such as tumor size, histologic grade, vascular invasion, and Ki-67 labeling index. The results suggest that reduced expression of p27Kip1 protein plays a role in biologically aggressive behavior of colorectal adenocarcinoma.

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 p27kip1 and Cyclin D1 in Serous Epithelial Ovarian Tumors.: Sun Young Kwon, Eun Sook Chang, Kun Young Kwon, Kwan Kyu Park, Soo Kyung Kim; Korean J Pathol. 2001;35(3):220-225.

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Abstract PDF: BACKGROUND
p27kip1 is a member of the Cip/Kip family of the cyclin-dependent kinase inhibitors and is a potential tumor suppressor gene. Decreased expression of p27kip1 is associated with high histologic grade and poor prognosis in a variety of human tumors.
METHODS
Sixty-six cases of serous epithelial ovarian tumors were investigated by immunohistochemical staining for p27kip1, cyclin D1, and Ki-67. Clinicopathologic parameters (WHO classification, histologic grade and FIGO stage) were compared with the incidence of p27kip1, cyclin D1 and Ki-67 protein expression in ovarian serous tumors.
RESULTS
Reduced expression of p27kip1 was found more freguently in serous cystadenocarcinoma than in serous cystadenoma and borderline malignancy (p<0.05). The decreased expression of p27kip1 was correlated with a high histologic grade and an advanced FIGO stage. Overexpression of cyclin D1 is associated with borderline malignancy and grade I serous cystadenocarcinoma. An inverse relationship was observed between the p27kip1 protein and the Ki-67 labeling index within serous cystadenocarcinoma, but it was not significant.
CONCLUSIONS
Reduced expression of p27kip1 protein plays an important role in the biologically aggressive behavior of serous epithelial ovarian tumors and might represent a useful prognostic marker for predicting the recurrence in primary ovarian tumors.

Correlation of Expression of galectin-3, skp2, p27 and cyclin D1 in Benign and Malignant Thyroid Lesions.: Soon Auck Hong, Min Eui Hong, Gui Young Kwon, Mi Kyung Kim; Korean J Pathol. 2008;42(3):134-139.

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Abstract PDF: BACKGROUND
The overexpression of cyclin D1 and galectin-3 and the loss of p27 in thyroid cancers have recently been reported by many studies. The S-phase kinase associated protein 2 (skp2) plays an important role in the degradation of p27. We compared the correlation of the expressions of galectin-3, p27, cyclin D1 and skp2 in thyroid lesions.
METHODS
Sixty five cases were included in this study and immunohistochemical staining for galectin-3, skp2, p27 and cyclin D1 was performed.
RESULTS
The expression of galectin-3 increased in the order of nodular hyperplasia, follicular adenoma, follicular carcinoma and papillary carcinoma (p<0.01). The expression rate of skp2 was 0% for nodular hyperplasia, 16.7% for follicular adenoma, 33.3% for follicular carcinoma and 16.7% for papillary carcinoma. The loss of the expression of p27 was more frequently detected in papillary carcinoma as compared with nodular hyperplasia (p<0.01). The increased expression of cyclin D1 was noted in follicular adenoma and carcinoma as compared with nodular hyperplasia (p=0.043). The expression of galectin-3 was related with the loss of a p27 expression (p<0.01), and the expression of skp2 was related with the expression of the cyclin D1 (p=0.022).
CONCLUSIONS
Galectin-3 appears to be the most useful marker for making the diagnosis of thyroid lesions. The loss of a p27 expression can help differentiate nodular hyperplasia and papillary carcinoma, and the determining the expression of cyclin D1 may be helpful for the differential diagnosis of nodular hyperplasia and follicular neoplasm.

Subcellular Localization of p27(kip1) in Breast Cancer and Its Prognostic Significance.: Sook Hee Hong, Dae Choel Kim, Se Heon Cho, Young Seoub Hong; Korean J Pathol. 2006;40(3):185-192.

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Abstract PDF: BACKGROUND
p27 is a member of the cyclin-dependent kinase (CDK) inhibitors that arrest the progression of the cell cycle; thus, it acts as a tumor suppressor gene. The loss or decrease of p27 protein is frequently seen and this has an independent prognostic potential for many human cancers. p27 is functionally inactivated through accelerated proteolysis and cytoplasmic sequestration. Cytoplasmic mislocalization of p27 by abnormal phosphorylation in the tumor cells doesn't allow it to bind and inhibit nuclear cyclin/CDK targets.
METHODS
We examined the p27 protein expression in 86 cases of invasive ductal carcinoma of the breast via immunohistochemical staining to evaluate the subcellular localization of p27 and its relationship with the clinicopathologic features and the prognostic factors.
RESULTS
The nuclear expression of p27 was noted in 48.9% of the tumors, a combined nuclear and cytoplasmic expression was noted in 20.9%, a cytoplasmic expression was noted in 12.8%, and a negative expression was noted in 17.4%. The decreased nuclear expression and/or cytoplasmic mislocalization of p27 were statistically correlated with the nuclear grade (p=0.001), histologic grade (p=0.036), tumor size (p=0.033), lymph node metastasis (p=0.043), ER (p=0.001), and PR (p=0.001) status, while they were not correlated with patient age, stage, HER2, p53, and Ki67.
CONCLUSIONS
The breast tumors showing both decreased nuclear expression and cytoplasmic mislocalization of p27 are associated with a deranged cell cycle via functional inactivation and also with poor prognostic factors. It is expected that p27 can be a promising anticancer target molecule for the treatment of breast cancer.

Expression of Heat Shock Protein 27 and Apoptosis in Renal Cell Carcinomas.: Ghil Suk Yoon; Korean J Pathol. 2006;40(1):39-45.

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Abstract PDF: BACKGROUND
Heat shock protein 27 (HSP27) is induced by heat shock and other pathophysiologic stresses, including neoplastic transformation. We examined the relationship between the HSP27 expression and the clinical and histologic parameters to elucidate the biologic and prognostic significance of HSP27 in renal cell carcinomas (RCCs). Its regulation of apoptosis in RCC development was also observed.
METHODS
We performed immunohistochemical studies for HSP27, caspase 3 and TUNEL on paraffin-embedded tissue microarray specimens from 48 RCCs.
RESULTS
There was a tendency to higher expression of HSP27 in the RCC than in normal renal tubular cells. Of the 48 RCCs, the HSP27 expression was positive in 38 cases. An inverse relationship was found between the Fuhrman nuclear grade and HSP27 expression, but this was without statistical significance (r=-0.218, p=0.093). No relationship between the HSP27 expression and the other parameters was observed. Also, no statistically significant difference was observed between apoptosis and the HSP27 expression more (p=0.951).
CONCLUSIONS
Although HSP27 expression was increased in RCC than in normal renal tubular cell the HSP27 expression may not be a powerful and statistically significant prognostic indicator in patients with RCC.

Expression of p34(cdc2), p27(Kip1), p21(WAF1/Cip1) and p53 in Human Breast Cancers.: Dong Hoon Kim, Chan Kum Park, Ho Jung Lee, Won Mi Lee, Eun Kyung Kim, Jong Eun Joo; Korean J Pathol. 2005;39(6):391-400.

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Abstract PDF: BACKGROUND
Cell cycle progression is governed by cell cycle regulators and inhibitors such as the cyclin dependent kinases (CDK), p27(Kip1), p21(WAF1/Cip1) and p53. The purpose of this study was to correlate expressions of p34(cdc2), p27(Kip1), p21(WAF1/Cip1) and p53 with the various clinicopathologic prognostic parameters of human breast cancers.
METHODS
The paraffin-embedded tissue sections from 102 patients with human breast carcinomas were examined by performing immunohistochemical staining. The primary antibodies used for immunohistochemical staining were mouse monoclonal antibody to human p34(cdc2), p27(Kip1), p21(WAF1/Cip1), p53, ER and PR.
RESULTS
The expression rates of p34(cdc2), p21(WAF1/Cip1) and p53 were 29.3%, 40.2% and 49.1% in breast carcinomas, respectively. In normal breast tissues, p34(cdc2), p21(WAF1/Cip1) and p53 were not expressed. The p34(cdc2) was expressed in the cytoplasm of cancer cells. The expression rate of p27(Kip1) was 29.3% in breast carcinomas and 100% in normal breast tissues, so the loss of p27(Kip1) expression in breast cancer was noted. The high expression of p21(WAF1/Cip1) in neoplastic cells was associated with the p53 expression (p=0.03). The expression of p27(Kip1) was correlated with that of the progesterone receptor (PR) (p=0.04) and the expression of p21(WAF1/Cip1) was correlated with that of positivity for estrogen receptor (ER) (p=0.04) and PR (p=0.04). No correlation was demonstrated between the mean patient survival and the expression rate of p34(cdc2), p27(Kip1), p21(WAF1/Cip1) and p53.
CONCLUSIONS
The loss of the normal cell growth cycle by the abnormal expression of cyclin dependent kinases and their inhibitors and the steroid hormones may play an important role in human breast carcinogenesis. The p53 dependent p21(WAF1/Cip1) pathway, the p27(Kip1) protein loss and the cdc2 overexpression were important in development and progression of human breast cancer.

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.

Analysis of Expression of p63 in Cervical Neoplasia Comparing with Other Immunohistochemical Markers .: Min Yeong Kim, Sam Hyun Cho, Moon Hyang Park; Korean J Pathol. 2003;37(5):333-341.

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Abstract PDF: BACKGROUND
The reproducibility in grading a cervical intraepithelial neoplasia (CIN) are not perfect. The aim of this study was to assess the value of the immunohistochemical expression of p63 and the other biomarkers for grading a CIN (dysplasia and in situ carcinoma), and diagnosing invasive carcinomas.
METHODS
Sixty six cervical specimens were immunostained with the monoclonal antibodies against p63, Ki-67, p27Kip1, and p53 to determine the localization.
RESULTS
The p63 positive cells are well linked with squamous cell maturation and the degree of dysplasia. In mild dysplasia, the p63 positive cells were localized to the basal and parabasal cells, which gradually extended into the middle and upper layers in moderate and severe dysplasia. p63 expression was strong in immature squamous epithelium and invasive squamous cells, but was constantly absent in an adenocarcinoma. The Ki-67 positive cells were scattered from the parabasal cells to the superficial cells in accordance with the degree of dysplasia. p27Kip1 expression was noted in the intermediate cells in the normal cervix. In CIN, the p27Kip1 positive nuclei tended to extend to the basal cells, but it showed no diagnostic consistency in an invasive carcinoma. p53 expression was also variable.
CONCLUSION
p63 is a useful diagnostic adjunct for grading CIN as well as for detecting microinvasion and squamous differentiation in invasive carcinoma. However, immunohistochemical expressions for the p27Kip1 and p53 have no correlation with the grade of CIN and squamous cell carcinoma.

Immunohistochemical Study of p27Kip1 Expression in Gastric Adenomas and Early Gastric Carcinomas: Analysis of 65 Cases.: Na Hye Myong; Korean J Pathol. 2003;37(5):325-332.

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Abstract PDF: BACKGROUND
Recent studies have suggested that loss of p27Kip1 expression correlates with poor prognosis in gastric carcinomas, although the published data is still controversial. However, there are very few reports on the immunohistochemical expression of p27Kip1 in gastric adenomas and its significance in the progression of gastric adenomas to early gastric carcinomas (EGCs) is unclear. We therefore performed an immunohistochemical study for p27Kip1 expression in gastric adenomas with low- and high-grade dysplasia and EGCs to investigate the role of p27Kip1 expression in gastric carcinogenesis.
METHODS
We collected 45 cases of endoscopic mucosal resection specimens which were diagnosed as gastric adenomas and 20 cases of gastrectomy specimens showing EGCs. Using a monoclonal antibody against p27Kip1, the im- munohistochemistry was performed on paraffin-embedded specimens.
RESULTS
The loss of p27Kip1 immunoreactivity (<5% of the tumor cells) tended to be observed more frequently in high-grade adenomas than in the low-grade. The loss was found significantly higher in the EGCs than in both high-grade and low-grade adenomas (p=0.000). Gastric adenomas with villous component showed significant loss of p27Kip1 expression (p=0.057).
CONCLUSION
These results suggest that loss of p27Kip1 expression can play a role in the progression of gastric adenomas into adenocarcinomas and the villous component allows reliable estimation of the possibility for malignant transformation.

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