Journal of Pathology and Translational Medicine

Original Articles

Basaloid Squamous Cell Carcinoma of the Head and Neck: Subclassification into Basal, Ductal, and Mixed Subtypes Based on Comparison of Clinico-pathologic Features and Expression of p53, Cyclin D1, Epidermal Growth Factor Receptor, p16, and Human Papillomavirus: Kyung-Ja Cho, Se Un Jeong, Sung Bae Kim, Sang-wook Lee, Seung-Ho Choi, Soon Yuhl Nam, Sang Yoon Kim; J Pathol Transl Med. 2017;51(4):374-380. Published online June 8, 2017; DOI: https://doi.org/10.4132/jptm.2017.03.03

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Background
Basaloid squamous cell carcinoma (BSCC) is a rare variant of squamous cell carcinoma with distinct pathologic characteristics. The histogenesis of BSCC is not fully understood, and the cancer has been suggested to originate from a totipotent primitive cell in the basal cell layer of the surface epithelium or in the proximal duct of secretory glands.
Methods
Twenty-six cases of head and neck BSCC from Asan Medical Center, Seoul, Korea, reported during a 14-year-period were subclassified into basal, ductal, and mixed subtypes according to the expression of basal (cytokeratin [CK] 5/6, p63) or ductal markers (CK7, CK8/18). The cases were also subject to immunohistochemical study for CK19, p53, cyclin D1, epidermal growth factor receptor (EGFR), and p16 and to in situ hybridization for human papillomavirus (HPV), and the results were clinico-pathologically compared.
Results
Mixed subtype (12 cases) was the most common, and these cases showed hypopharyngeal predilection, older age, and higher expression of CK19, p53, and EGFR than other subtypes. The basal subtype (nine cases) showed frequent comedo-necrosis and high expression of cyclin D1. The ductal subtype (five cases) showed the lowest expression of p53, cyclin D1, and EGFR. A small number of p16- and/or HPV-positive cases were not restricted to one subtype. BSCC was the cause of death in 19 patients, and the average follow-up period for all patients was 79.5 months. Overall survival among the three subtypes was not significantly different.
Conclusions
The results of this study suggest a heterogeneous pathogenesis of head and neck BSCC. Each subtype showed variable histology and immunoprofiles, although the clinical implication of heterogeneity was not determined in this study.

Citations

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HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management
Matt Lechner, Jacklyn Liu, Liam Masterson, Tim R. Fenton
Nature Reviews Clinical Oncology.2022; 19(5): 306. CrossRef
Neoadjuvant treatment combined with planned endoscopic surgery in locally advanced sphenoid sinus basaloid squamous cell carcinoma
Yinghong Zhang, Suqing Tian, Yali Du, Qiang Zuo, Li Zhu, Furong Ma
Medicine: Case Reports and Study Protocols.2022; 3(6): e0044. CrossRef
Cetuximab and paclitaxel combination therapy for recurrent basaloid squamous cell carcinoma in the ethmoid sinus
Satoshi Koyama, Kazunori Fujiwara, Tsuyoshi Morisaki, Taihei Fujii, Yosuke Nakamura, Takahiro Fukuhara, Hiromi Takeuchi
Auris Nasus Larynx.2021; 48(6): 1189. CrossRef
Constitutive Hedgehog/GLI2 signaling drives extracutaneous basaloid squamous cell carcinoma development and bone remodeling
Marina Grachtchouk, Jianhong Liu, Mark E Hutchin, Paul W Harms, Dafydd Thomas, Lebing Wei, Aiqin Wang, Donelle Cummings, Lori Lowe, Jonathan Garlick, James Sciubba, Arul M Chinnaiyan, Monique E Verhaegen, Andrzej A Dlugosz
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Conjunctival ‘mucoepidermoid carcinoma’ revisited: a revision of terminology, based on morphologic, immunohistochemical and molecular findings of 14 cases, and the 2018 WHO Classification of Tumours of the Eye
Hardeep S. Mudhar, Tatyana Milman, Paul J.L. Zhang, Carol L. Shields, Ralph C. Eagle, Sara E. Lally, Jerry A. Shields, Sachin M. Salvi, Paul A. Rundle, Jennifer Tan, Ian G. Rennie
Modern Pathology.2020; 33(7): 1242. CrossRef
Basaloid squamous cell carcinoma with adenoid cystic‐like features of the head and neck region: A report of two cases
Kimihide Kusafuka, Haruna Yagi, Satoshi Baba, Hiroshi Inagaki, Chinatsu Tsuchiya, Kazuki Hirata, Aya Muramatsu, Makoto Suzuki, Kazumori Arai, Tadashi Terada
Pathology International.2020; 70(10): 767. CrossRef
Association study of cell cycle proteins and human papillomavirus in laryngeal cancer in Chinese population
Lifang Cui, Congling Qu, Honggang Liu
Clinical Otolaryngology.2019; 44(3): 323. CrossRef
Liver metastatic basaloid squamous cell carcinoma with negative expression of pancytokeratin: a case report and literature review
Linxiu Liu, Xuemin Xue, Liyan Xue
Diagnostic Pathology.2019;[Epub] CrossRef
Basaloid Squamous Cell Carcinoma at the Floor of the Mouth and Mandible: A Case Report
Jun-Sang Lee, Uk-Kyu Kim, Dae-Seok Hwang, Jun-Ho Lee, Hong-Seok Choi, Na-Rae Choi, Mi Heon Ryu, Gyoo Cheon Kim
The Korean Journal of Oral and Maxillofacial Pathology.2019; 43(5): 197. CrossRef
p53 and p16 expression in oral cavity squamous cell and basaloid squamous cell carcinoma
Allisson Filipe Lopes Martins, Carlos Henrique Pereira, Marília Oliveira Morais, Paulo Otávio Carmo Souza, Lucas Borges Fleury Fernandes, Aline Carvalho Batista, Elismauro Francisco Mendonça
Oral Cancer.2018; 2(1-2): 7. CrossRef
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Xinsheng Lin, Guofeng Wen, Shuangle Wang, Hangui Lu, Chuangwei Li, Xin Wang
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Expression of Human Papillomavirus-Related Proteins and Its Clinical Implication in Tonsillar Squamous Cell Carcinoma: Joon Seon Song, Min-Sik Kim, Joon Wook Park, Youn Soo Lee, Chang Suk Kang; Korean J Pathol. 2012;46(2):177-186. Published online April 25, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.2.177

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Abstract PDF

Background

Human papillomavirus (HPV) is known to cause of oropharyngeal squamous cell carcinoma (SqCC). HPV positive SqCCs overexpress p16 and are associated with better survival. Several markers of cell cycles and apoptosis have been reported as a prognostic value. We examined the prognostic value of HPV status, p16, cyclin D1, and Bcl-2 in patients with tonsillar SqCC.

Methods

Tissue microarrays were constructed in 56 cases of tonsillar SqCC for which we performed an immunohistochemistry and an in situ hybridization (ISH) of the HPV.

Results

Of the 56 cases, 31 (55.3%) were positive for p16 and 20 (35.7%) were positive for HPV ISH. The expressions of p16, cyclin D1, and Bcl-2 were not correlated with the clinicopathologic variables including smoking status, differentiation and pT- and pN-stages. The HPV ISH positive group showed a better overall survival than the HPV negative group (p=0.04), and the p16 positive group showed a better disease free survival (DFS) than the negative group (p=0.016). Cox regression analysis showed that only p16 positivity was an independent prognostic factor for DFS (p=0.03; hazard ratio, 10.1).

Conclusions

Our results indicate that both p16 expression and HPV status are useful indicators for risk stratification in patients with tonsillar SqCC.

Citations

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Positive Rate of Human Papillomavirus and Its Trend in Head and Neck Cancer in South Korea
Hyun Woong Jun, Yong Bae Ji, Chang Myeon Song, Jae Kyung Myung, Hae Jin Park, Kyung Tae
Frontiers in Surgery.2022;[Epub] CrossRef
Negative Prognostic Implication of TERT Promoter Mutations in Human Papillomavirus–Negative Tonsillar Squamous Cell Carcinoma Under the New 8th AJCC Staging System
Hyunchul Kim, Mi Jung Kwon, Bumjung Park, Hyo Geun Choi, Eun Sook Nam, Seong Jin Cho, Kyueng-Whan Min, Eun Soo Kim, Hee Sung Hwang, Mineui Hong, Taeryool Koo, Hyo Jung Kim
Indian Journal of Surgical Oncology.2021; 12(S1): 134. CrossRef
In situ hybridization for high risk HPV E6/E7 mRNA in oropharyngeal squamous cell carcinoma
Krish Suresh, Parth V. Shah, Sydney Coates, Borislav A. Alexiev, Sandeep Samant
American Journal of Otolaryngology.2021; 42(1): 102782. CrossRef
Prevalence of high-risk human papillomavirus and its genotype distribution in head and neck squamous cell carcinomas
Yuil Kim, Young-Hoon Joo, Min-Sik Kim, Youn Soo Lee
Journal of Pathology and Translational Medicine.2020; 54(5): 411. CrossRef
Human Papillomavirus Testing in Head and Neck Carcinomas: Guideline From the College of American Pathologists
James S. Lewis, Beth Beadle, Justin A. Bishop, Rebecca D. Chernock, Carol Colasacco, Christina Lacchetti, Joel Todd Moncur, James W. Rocco, Mary R. Schwartz, Raja R. Seethala, Nicole E. Thomas, William H. Westra, William C. Faquin
Archives of Pathology & Laboratory Medicine.2018; 142(5): 559. CrossRef
Detection of HPV infection in head and neck cancers: Promise and pitfalls in the last ten years: A meta-analysis
Carolin G�tz, Clara Bischof, Klaus-Dietrich Wolff, Andreas Kolk
Molecular and Clinical Oncology.2018;[Epub] CrossRef
Frequent hepatocyte growth factor overexpression and low frequency of c-Met gene amplification in human papillomavirus–negative tonsillar squamous cell carcinoma and their prognostic significances
Mi Jung Kwon, Dong Hoon Kim, Hye-Rim Park, Hyung Sik Shin, Ji Hyun Kwon, Dong Jin Lee, Jin Hwan Kim, Seong Jin Cho, Eun Sook Nam
Human Pathology.2014; 45(7): 1327. CrossRef
Human papillomavirus‐stratified analysis of the prognostic role of miR‐21 in oral cavity and oropharyngeal squamous cell carcinoma
Yoon Ho Ko, Hye Sung Won, Der Sheng Sun, Ho Jung An, Eun Kyoung Jeon, Min Sik Kim, Han Hong Lee, Jin Hyoung Kang, Chan Kwon Jung
Pathology International.2014; 64(10): 499. CrossRef
Human Papillomavirus Prevalence and Cell Cycle Related Protein Expression in Tonsillar Squamous Cell Carcinomas of Korean Patients with Clinicopathologic Analysis
Miji Lee, Sung Bae Kim, Sang-wook Lee, Jong-Lyel Roh, Seung-Ho Choi, Soon Yuhl Nam, Sang Yoon Kim, Kyung-Ja Cho
Korean Journal of Pathology.2013; 47(2): 148. CrossRef

Functional Inactivation of pRb Associated with Cyclin D1- and Cyclin-dependent Kinase 4 Overexpression Plays A Key Role in Human Pituitary Tumorigenesis.: Na Hye Myong; Korean J Pathol. 2009;43(1):56-62.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.1.56

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Abstract PDF

BACKGROUND
Human pituitary adenoma (PA) is a common intracranial tumor, but the mechanism underlying tumorigenesis has not been established. Functional inactivation of retinoblastoma protein (pRb) following cyclin D1- and cyclin-dependent kinase (CDK) 4-dependent hyperphosphorylation is one of the most important mechanisms in tumor cell proliferation. We evaluated immunohistochemical expressions of cyclin D1, CDK4 and phosphorylated pRb (p-pRb) in 50 PAs to investigate a role for functional inactivation of pRb associated with cyclin D1/CDK4 overexpression in pituitary tumorigenesis and to correlate it with clinicopathologic variables.
METHODS
Fifty human PAs were immunohistochemically stained for cyclin D1, CDK4 and p-pRb (Thr 356). Correlations between their expression and the clinicopathologic characteristics were statistically analyzed.
RESULTS
Cyclin D1 and CDK4 were overexpressed in 56% and 64%, respectively; pRb was hyperphosphorylated in 64%. Forty one cases (82%) showed one or more of these altered expressions. Overexpressions of cyclin D1 and CDK4 were correlated with functional pRb inactivation. Cyclin D1 overexpression was associated with apoplexy and growth hormone production.
CONCLUSIONS
Functional inactivation of pRb associated with the cyclin D1/CDK4 overexpression might play a key role in human pituitary tumorigenesis. CDK4 worked in concert with cyclin D1 to hyperphosphorylate pRb. Pituitary apoplexy appeared to be associated with cyclin D1 overexpression.

Citations

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Differential expression of cyclin D1 in human pituitary tumors: relation to MIB-1 and p27/Kip1 labeling indices
Iman H. Hewedi, Wesam M. Osman, Manal M. El Mahdy
Journal of the Egyptian National Cancer Institute.2011; 23(4): 171. CrossRef

Cyclin D1 Expression in 101 Cases of Breast Carcinoma.: Duck Hwan Kim, Eun Sook Nam, Hyung Sik Shin, Jin Woo Ryu, Jai Hyang Go, Young Lyun Oh, Sang Yong Song, Dae Shick Kim, Min Chul Lee; Korean J Pathol. 1998;32(4):266-272.

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Abstract PDF: Cyclin D1, a cell cycle regulator essential for G1 phase progression, is a candidate proto-oncogene implicated in pathogenesis of several human carcinomas including breast carcinoma. We studied the cyclin D1 expression in 101 cases of primary breast carcinoma tissues. The overexpression of cyclin D1 was immunohistochemically demonstrated in 34 (37.8%) of 90 cases of invasive breast carcinoma. Positive cyclin D1 staining was seen in 32 of 79 invasive ductal carcinomas, and 2 of 3 mucinous carcinomas. All 5 medullary carcinomas, 2 invasive lobular carcinomas, and 1 metaplastic carcinoma were negative. Cyclin D1 overexpression was observed in 9 of 11 ductal carcinoma in situ (DCIS). Normal epithelial components, either ductal or lobular, were not immunoreactive for cyclin D1. No significant correlations were observed between cyclin D1 immunoreactivity and other parameters including tumor size, clinical stage, nuclear or histologic grades, lymphatic or angioinvasion, lymph node metastasis, and immunohistochemical status of progesterone receptor, p53 and c-erbB-2. The overexpression of cyclin D1 was positively correlated with estrogen receptor status (p=0.025). Based on our results, the cyclin D1 protein aberration may play a role in tumorigenesis of breast carcinoma, but does not seem to have prognostic value in invasive breast carcinoma without hormonal treatment.

The Value of Immunohistochemistry on Paraffin Embedded Tissue Sections in the Differentiation of Subgroups of Low Grade B-Cell Lymphomas.: Tae Sook Hwang, Seung Sook Lee, Ji Eun Kim, Hye Seung Han, Chul Woo Kim; Korean J Pathol. 1998;32(12):1066-1073.

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Abstract: There had been a continuous evolution of lymphoma classification and recently a Revised European-American Lymphoma Classification was proposed by the International Lymphoma Study Group. This new classification often requires information on immunophenotypic and molecular biologic markers in addition to the usual histologic findings. Recent advances in the production of commercially available monoclonal antibodies reactive on formalin-fixed paraffin-embedded tissues provide us a great help to classify the non-Hodgkin's lymphoma. We have analyzed 31 low grade B-cell lymphomas by the schemes proposed by the International Lymphoma Study Group using antibodies to CD3, CD5, CD20, CD23, CD43, cyclin D1, and bcl-2 protein, and have analyzed the immunophenotypic features. Among 31 low grade B-cell lymphomas, 8 small lymphocytic lymphomas, 5 mantle cell lymphomas, 7 follicle center lymphomas (2 grade I, 3 grade II, and 2 grade III), and 11 marginal zone B-cell lymphomas (all of which were extranodal) were identified. Among 8 small lymphocytic lymphomas, 5 cases were positive for CD5; 6 cases were positive for CD23; 7 cases were positive for CD43; all 8 cases were negative for cyclin D1; and 7 cases were positive for bcl-2. Among 5 mantle cell lymphomas, 4 cases were positive for CD5 and CD43; all five cases were negative for CD23; 4 cases were positive for cyclin D1 and bcl-2. All 7 follicle center lymphomas were negative for CD5, CD43 and cyclin D1 and 2 cases were positive for CD23; and 6 cases were positive for bcl-2. All marginal zone B-cell lymphomas were negative for CD5, CD23 and cyclin D1; 3 cases were positive for CD43 and 9 cases were positive for bcl-2. Diagnostic utility for CD5 antigen detection on paraffin embedded tissue has a limitation due to weak antigen expression in tumor cells of B-cell lymphomas; however, still be useful in differentiating small lymphocytic lymphoma and mantle cell lymphoma from other B-cell lymphomas when applied in conjunction with CD43. CD23, CD43, and cyclin D1 appear to be of great help in differentiating subgroups of low grade B-cell lymphomas. Bcl-2, as known, is found to be useful to rule out reactive follicular hyperplasia.

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.

Relationship among the Expression of Cyclin D1, p21, and p53 Protein, and Prognosis in Non-Small Cell Lung Carcinomas.: Seok Woo Yang, Sang Ho Cho, Woo Ick Yang, Woo Hee Jung, Chul Min Ahn, Doo Yun Lee; Korean J Pathol. 1999;33(12):1120-1130.

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Abstract PDF: Recently, cell cycle regulators have been suggested as new prognostic factors of the lung cancer. In this study, we evaluated the expression of cyclin D1, p21, and p53 using the X2-test, with regard to the stage of the patients, histologic type, and histologic differentiation in the 135 cases of non-small cell lung carcinomas (NSCLC). To evaluate the confounding effects among cyclin D1, p21, and p53 on X2-test analysis, we used the Mantel-Haenzel test. The NSCLC in this study included 82 cases of squamous cell carcinoma and 53 cases of adenocarcinoma. Each nuclear staining of cyclin D1, p21, and p53 was observed in 65 cases (48.1%), in 54 cases (40.0%), and in 81 cases (60.0%) of NSCLCs, respectively. Only p53 expression was significantly associated with the stage (stage I, II, IIIa) (p<0.05) and squamous cell carcinoma (p<0.05). On the other hand, cyclin D1 expression was significantly associated with the histologic differentiation. The confounding effects among cyclin D1, p21, and p53 revealed that only p21 expression changed the relationship between p53 and stage. In this regard, further study is needed.

Classification of Gastrointestinal B-cell Lymphoma and Expression of Cyclin D1, bcl-2, bcl-6, p53 Protein and PCNA.: Ji Han Jung, An Hee Lee, Chang Suk Kang, Byung Kee Kim; Korean J Pathol. 2000;34(6):437-445.

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Abstract PDF: Until recently, the gastrointestinal lymphomas were classified according to the criteria developed for the node-based lymphomas. In recent years, the REAL classification provided a new category of MALT lymphoma and Mantle cell lymphoma in B-cell lymphomas. Low-grade MALT lymphomas have been well characterized clinically, histologically, and immunophenotypically. We retrospectively recategorized 41 cases of the primary gastrointestinal B-cell lymphoma and investigated the expression of cyclin D1, bcl-2, bcl-6, p53 protein, and PCNA by immunohistochemical method. The cases were categorized in 5 groups, low grade MALToma, low/high grade MALToma, high grade MALToma, diffuse large cell lymphoma, and mantle cell lymphoma according to the morphological findings. The expression of cyclin D1 protein was restricted to the cases of mantle cell lymphoma. The bcl-2 protein expression was higher in the low grade MALT lymphoma than in the high grade lymphoma (P=0.006). The bcl-2 protein expression was higher in the low grade area than in the high grade area in the low/high grade MALT lymphoma (P=0.005). The bcl-6 and p53 protein expression was higher in the high grade MALT lymphoma than in the low grade lymphoma (P=0.022, P<0.018). However, the bcl-6 protein expression of the tumor cells was higher in high grade area than in low grade area in the low/high grade MALT lymphoma (P=0.004). The degree of the PCNA expression was positively correlated with the grade of the malignant lymphoma (P=0.003). The above results suggest that the cellular proliferation assessed by PCNA index correlates with the histologic grade. And the bcl-2, bcl-6, p53 protein may be effective in the transition from the low grade MALT lymphoma to the high grade lymphoma. Therefore, we can differentiate the low grade lymphoma from the high grade lymphoma by the immunohistochemical staining for cyclin D1, bcl-2, bcl-6, p53 protein and can predict the prognosis of the patients in accordance with the grade of the tumor.

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.

Expression of Chromogranin A, Cathepsin D, Cyclin D1 and p53 proteins in Colorectal Adenocarcinoma.: Chae Hong Suh, Mi Ja Lee, Sung Kang Cho; Korean J Pathol. 2001;35(1):7-13.

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Abstract PDF: BACKGROUND
The purpose of this study is to assess the roles of chromogranin A, cathepsin D, cyclin D1 and p53 protein expression in colorectal tumorigenesis.
METHODS
83 colorectal cancer and 12 villotubular adenoma tissue specimens were investigated by immunohistochemical staining for chromogranin A, cathepsin D, cyclin D1 and p53 protein. Clinicopathologic values (tumor size, histologic grade, Astler-Coller stage and lymph node metastasis) were compared with the incidence of chromogranin A, cathepsin D, cyclin D1 and p53 protein expression in colorectal adenocarcinomas.
RESULTS
Statistically significant correlation was noted between the expression of chromogranin A and histologic grade (p<0.05). The incidence of positive cathepsin D expression was increased with tumor size (p<0.05), and there was a statistically significant correlation between histologic grade and cathepsin D expression (p<0.005). There were no statistically significant correlations among cyclin D1 expression and tumor size, histologic grade, stage and lymph node metastasis. Patients with lymph node metastasis had a high incidence of positive p53 protein expression compared to those without this finding (p<0.001).
CONCLUSION
It is suggested that chromogranin A, cathepsin D, and p53 protein are useful variables for the prognostic assessment of colorectal adenocarcinoma. The p53 protein seems to involve the metastatic ability of colorectal adenocarcinomas. Also, the expression of cathepsin D, cyclin D1, and p53 protein may play an important role in the tumorigenesis and progression of the colorectal adenoma-carcinoma sequence.

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.

Expression of Cyclin D1, CDK4, p16 and Rb Proteins in Human Soft Tissue Sarcomas.: Jinyoung Yoo, Ah Won Lee, Seok Jin Kang, Byung Kee Kim; Korean J Pathol. 2001;35(3):238-244.

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Abstract PDF: BACKGROUND
Altered cell cycle regulation may underlie the development and/or progression of human malignancies. The purpose of this study is to determine if the oncogenesis of soft tissue sarcomas could be better explained by examining the components involved in G1 phase progression.
METHODS
Sixty-seven soft tissue sarcomas were studied for the immunohistochemical expression of cdk4, cyclin D1, retinoblastoma (Rb) and p16 proteins. For Rb and p16, samples showing either negative or heterogeneous (<80% of tumor cells) staining were considered to be altered.
RESULTS
The cdk4 protein was observed in 64 cases (95.5%). Cyclin D1 was expressed in 14 cases (20.9%). The Rb expression was altered in 48 (71.6%). Sixty-three (94%) sarcomas demonstrated altered p16 expressions. All of the samples displayed altered expressions of either Rb or p16. A high percentage of the tumors with altered Rb were observed in relapsed patients (p<0.05).
CONCLUSIONS
Disturbance in the cell cycle regulatory system involving the Rb/p16/cdk4/cyclin D1 pathway appears to be relatively frequent in soft tissue sarcomas and may play an important role in the tumorigenesis of these tumors. It is noteworthy that the reduced Rb expression correlates with tumor relapse, suggesting its prognostic significance.

K-ras Gene Mutations and Expression of K-ras, p16, Cyclin D1 and p53 in Synchronous Lesions of The Colon Adenoma-Carcinoma Sequences.: Hwa Eun Oh, Seong Jin Cho, Nam Hee Won, Dale Lee, Insun Kim, Bom Woo Yeom; Korean J Pathol. 2001;35(4):291-298.

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Abstract PDF: BACKGROUND
The colorectal adenoma-carcinoma sequence represents a well-known para-digm for the sequential development of cancer driven by the accumulation of genomic defects. Although the colorectal adenoma-carcinoma sequence has been well investigated, the studies about tumors of different dignity co-existent in the same patient are rare. K-ras mutation is an early genetic change in colon cancer. The genes involved in the cell cycle such as cyclin D1, p16, and p53 are important in the tumorigenesis of the colon. The aims of this study were to determine K-ras gene mutation and expression of K-ras, p16, cyclin D1 and p53 in synchronous lesions of the colon adenoma-carcinoma sequences and their possible relationship with K-ras mutation.
METHODS
The materials included 45 colonic adenocarcinomas which were accompanied by adenoma (22 low grade and 26 high grade). By using polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP), we detected K-ras mutation of codon 12. An aberrant K-ras, p16, cyclin D1 and p53 expressions were stained using an immunohistochemical method. RESULTS: K-ras mutation was 52.4% (11/21) of high grade adenomas. K-ras expression was 65.4% (17/26) of high grade adenomas. p16 and cyclin D1 expressions were 50% (11/22) and 90.9% (20/22) of low grade adenomas, respectively. p53 expression was 75.6% (34/45) of adenocarcinomas. There were statistical correlations among K-ras, p16 and cyclin D1.
CONCLUSIONS
These results indicate that the ras gene mutation is an early event and the overexpressions of p16, cyclin D1 and p53 are associated with K-ras mutation and expression in adenoma-carcinoma sequences.

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

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

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.

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