Expression of BCL-2 and p53 in oncocytic (Hürthle cell) tumors of the thyroid: An immunohistochemical study

Previous studies have established that thyroid follicular neoplasms of higher malignant potential show a high p53 and low bc1-2 expression. This however has not been well studied in Oncocytic (Hürthle cell) neoplasms, the management of which remains controversial. We therefore studied the expression of p53 and bc1-2 in 18 Hürthle cell adenomas (HCA) and 8 Hürthle cell carcinomas (HCC) and compared them with their benign and malignant counterparts, respectively, including 16 follicular adenomas (FA) and 68 papillary carcinomas (PC). All 16 FA were bc1-2 positive, 4 were 2+, and 12 were 3+. On the other hand, 14/18 (78%) HCA showed bc1-2 expression, 5 were 1+, 6 were 2+, and only 3 were 3_. Similarly, HCC showed a weaker bc1-2 staining pattern compared to PC. Only 1 FA showed grade 1, p53 staining, the remaining 15 were negative, and 15/18 HCA showed p53 expression of varying grades. This difference in p53 staining was statistically significant (p=0.005). A significant p53 overexpression was also seen in HCC compared to PC (p=0.005). In conclusion, there appears to be an inverse relationship between p53 and bc1-2 expression in thyroid follicular neoplasms. A higher expression of p53 and lower levels bc1-2 in Hürthle cell neoplasms may have biological and clinical implications. This may support a more aggressive surgical treatment for HCA compared to FA.     

Cyclin A correlates with carcinogenesis and metastasis,and p27(kip1) correlates with lymphatic invasion,in colorectal neoplasms

Cyclin A binds to CDK2 and plays critical roles when cells proliferate; staining for Ki67 can monitor the proliferation. The cyclin A expression pattern remains unclear in colorectal carcinogenesis and remote metastasis, however, and no one has reported on the association of its expression with key clinicopathologic factors in primary cancer. p27(kip1) protein-an extremely important inhibitor of CDK2-seems unchanged as colorectal cancers metastasize to the lymph nodes, a result contrary to that seen in gastric and prostatic cancers. To clarify the role of cyclin A in multistage colorectal neoplasms, cyclin A, CDK2, and Ki67 were immunohistochemically stained in 22 normal mucosa, 9 hyperplastic polyps, 61 adenomas, 197 primary carcinomas, 21 lymph node metastases, and 10 hepatic metastases. To clarify the alteration of p27(kip1) during lymphatic invasion, p27(kip1) was also stained in 21 primary cancers and paired lymph node foci. Situated in nuclei, cyclin A expression gradually increased from mild through moderate to severe dysplasia in adenomas and from normal tissue through hyperplasia to adenoma to early carcinoma. Expression was significantly decreased in the hepatic metastases and in the primary cancers showing venous invasion, deep infiltration, lymph node metastasis, mucinous type, advanced stage, or short postoperative survival time. Elevated cyclin A not only was linked with elevated CDK2 in primary cancers, but also was associated with increased Ki67 in both adenomas and primary carcinomas. Lymph node metastases lost more p27(kip1) than primary foci and hepatic lesions. Thus, dysregulation of cyclin A and its control mechanisms may contribute to colorectal carcinogenesis; abatement of overexpression of cyclin A is associated with hepatic metastasis and cancerous invasion. Loss of p27(kip1) may promote lymph node metastasis.     

The role of cell cycle regulatory protein, cyclin D1, in the progression of thyroid cancer.

Cell cycle progression is facilitated by cyclin-dependent kinases that are activated by cyclins including cyclin D1 and inactivated by cyclin-dependent kinase inhibitors (CDKIs) such as p27. Our previous studies have demonstrated decreased p27 expression in both papillary and more aggressive carcinomas of the thyroid compared to thyroid adenoma and almost similar level of cyclin D1 expression between thyroid adenoma and papillary carcinoma. These results indicate that CDKIs may have an important role in the carcinogenesis of the thyroid and that they probably have a limited role in malignant progression of the thyroid cancer. The role of cyclin D1 in malignant progression of thyroid carcinoma has yet to be established. We studied the expression of cyclin D1 by immunohistochemistry in 34 cases of conventional papillary carcinoma (CPC), 10 cases of minimally invasive follicular carcinoma (MIFC), and 32 cases of more aggressive thyroid carcinoma (ATC), which included 11 tall cell variants, one columnar cell variant of papillary carcinoma, seven insular carcinomas, and 13 anaplastic carcinomas. Cyclin D1 staining was classified by staining score as 0, negative; 1+, less than 25%; 2+, 25 to 50%; and 3+, more than 50% tumor cells staining positive. Kruskal-Wallis one-way ANOVA and Wilcoxon Rank Sum/Mann-Whitney U Test was used to assess the difference in the expression of cyclin D1 between the study groups. Twenty-eight out of the 34 CPCs were cyclin D1 positive, 24 (70%) were 1+, 3 (9%) were 2+, and one (3%) were 3+ positive. Seven of 10 MIFCs were cyclin D1 positive, five (71%) were 1+, and the remaining two (29%) were 2+ positive. On the other hand, 28 of 32 ATCs showed cyclin D1 immunostaining. Of these, three (9%) were 1+, five (13%) were 2+, and 20 (63%) were 3+ positive. This study demonstrates a significant overexpression of cyclin D1 in ATC compared CPC (P < .001) and MIFC (P < .005), suggesting that the cyclin D1 expression may play a role in tumor progression and may have prognostic significance in thyroid cancer.     

Altered expression of key cell cycle regulators in renal cell carcinoma associated with Xp11.2 translocation

Renal cell carcinoma (RCC) is a rare tumor in the pediatric population. Recently, a phenotypically and genetically distinct kidney carcinoma, mainly prevalent in children and associated with an Xp11.2 translocation or TFE3 gene fusion, has been described. It has been advanced that in this subtype of RCC, there is an accumulation of cyclin D1, cyclin D3, and p21 ^(wafl/cip1). The aim of the present study was to figure out in two pediatric RCC recently diagnosed in our department (one clear cell-type RCC and one TFE3-positive RCC) whether those features are indeed specific of the latter tumor or occur in pediatric RCC irrespective of the tumor type. The following immunostains were performed in both cases: Ki67, p16^ink4a, p21 ^(wafl/cip1), p27^kip1, p53, p63, mdm2, cyclin D1, cyclin D3, TFE3, CD10, vimentin, E-cadherin, and RCC-antigen. We observed in the TFE3-positive carcinoma an intense immunoreaction for p21 ^(wafl/cip1), cyclin D1, and cyclin D3, without expression for p53, p16, p27^kip1, and mdm2, whereas the immunoexpression profile observed in the classic RCC was similar to that of clear cell, adult-type RCC.     

Oncocytic thyroid neoplasms: from histology to molecular biology

The recent update of the 4th edition of the World Health Organization's Classification of Tumors of Endocrine Organs introduced important changes in the nomenclature of follicular-cell thyroid tumors, namely, regarding mitochondrion-rich neoplasms (In this review, for the practical purposes, the words Hürthle and oncocytic are synonymous in the field of thyroid pathology.) According to the last edition, oncocytic thyroid neoplasms, with follicular architecture and no typical nuclei of papillary carcinoma, – are now included in a separate group - the Hürthle cell neoplasms. Whenever thus categorized-while keeping oncocytic variant of papillary, medullary and poorly differentiated carcinoma-, a sort of tidal phenomenon has occurred about oncocytic tumors known for decades. Through this categorization, pathologists and researchers need to progress in the discussion about etiopathogenesis of oncocytic neoplasms (ONs). This review provides an attempt to balance the facts and doubts by questioning the recent changes based on what is known about oncocytic tumors.     

Cumulative alterations of p27Kip1‐related cell‐cycle regulators in the development of endometriosis‐associated ovarian clear cell adenocarcinoma

Yamamoto S, Tsuda H, Miyai K, Takano M, Tamai S & Matsubara O
(2010) Histopathology 56, 740–749
Cumulative alterations of p27 ^Kip1 ‐related cell‐cycle regulators in the development of endometriosis‐associated ovarian clear cell adenocarcinoma Aims: To identify the key cell‐cycle dysregulations in the development of endometriosis‐associated ovarian clear cell adenocarcinoma (CCA). Methods and results: Expression of p27^Kip1‐interacting cell‐cycle regulators, such as p27^Kip1 itself, Skp2, cyclin‐dependent kinase subunit 1 (Cks1), cyclin A and cyclin E, and Ki67 labelling index (LI), were analysed by immunohistochemistry in 23 CCAs with 36 endometriotic or atypical endometriotic lesions adjacent to CCA from a cohort of 23 patients, and in 31 cases of solitary endometriosis. The cell‐cycle regulators examined were overexpressed (Skp2, Cks1, cyclin A and cyclin E; P < 0.01, each) or down‐regulated (p27^Kip1, P = 0.044) significantly more frequently in the CCAs than in the adjacent endometriosis. The frequency of Skp2 overexpression was significantly higher in atypical endometriosis than in endometriosis, and the frequency of Skp2 and cyclin A overexpression was significantly higher in CCA than in atypical endometriosis (P < 0.01, each). Mean Ki67 LI increased from endometriosis (8.4%) through atypical endometriosis (21.4%) to CCA (46.9%), with statistical significance between each component (P < 0.01, each). The frequency of cell‐cycle regulator expression and mean Ki67 LIs were not significantly different between solitary endometriosis and endometriosis adjacent to CCA. Conclusions: Alteration of the p27^Kip1‐interacting cell‐cycle regulators appeared strongly involved in the progression of endometriosis‐associated ovarian clear cell carcinogenesis through increasing cell proliferative activity.     

Differential expression of cdk inhibitors p16, p21cip1, p27kip1, and cyclin E in cervical cytological smears prepared by the ThinPrep method

Our objective was to correlate p16, p21cip1, p27kip1, and cyclin E protein expression with the degree of dysplasia on ThinPrep Papanicolaou (Pap) smears using a modified immunoperoxidase staining. Smears read as normal, atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion (LSIL), or high-grade SIL (HSIL) were identified and tested for high-risk human papillomavirus (HR-HPV). Additional smears were processed for immunoperoxidase for p16, p21cip1, p27kip1, and cyclin E. Thirty-four smears were satisfactory for study. The p16 was positive in all nine HSIL, in four of nine LSIL, and in one of seven ASC-US. The p27kip1 was positive in all nine HSIL, in eight of nine LSIL, and in one of seven ASC-US. The p21cip1 was positive in all nine HSIL, in one of nine LSIL, and in one of seven ASC-US. Cyclin E was positive in seven of nine HSIL and in one of nine LSIL and in none of the ASC-US smears. Normal smears were negative for all the antigens. There was poor correlation of protein expression and HR-HPV infection. We concluded that p16, p21cip1, p27kip1, and cyclin E can be demonstrated on Pap smears and they are expressed differentially in dysplastic cells, with highest expression in HSIL. The p21cip1 and cyclin E showed the greatest correlation with HSIL.     

肾癌中cyclinD1和p27kip1的表达及其意义

目的探讨cyc lin D1、p27k ip1在普通型肾细胞癌(renal cell carc inom a,RCC)发生、发展中的作用。方法用半定量RT-PCR方法检测25例普通型RCC和10例肿瘤远端的正常肾组织中cyc lin D1的mRNA含量,用免疫组化方法检测76例普通型RCC中cyc lin D1和p27k ip1蛋白的表达,并对cyc lin D1、p27k ip1蛋白表达与临床病理参数的关系进行分析。结果普通型RCC中cyc lin D1的mRNA含量0.488±0.399,高于正常对照组0.089±0.066(P<0.01)。cyc lin D1的表达与肿瘤体积大小有关,体积大者cyc lin D1高表达(P<0.05)。普通型RCC中p27k ip1表达低于正常对照组,随着p27k ip1表达的降低,肿瘤的细胞核Fu-hrm an分级、TNM分期增高。结论cyc lin D1高表达和p27k ip1的低表达与普通型RCC的发生有关;p27k ip1的低表达可能促进肿瘤的演进,p27k ip1的表达可作为评价普通型RCC预后的参考指标。     

Diagnostic criteria in well-differentiated thyroid carcinomas

The criteria used for the differential diagnosis of well-differentiated thyroid tumors derived from follicular cells are reviewed taking into account the architectural characteristics together with the immunohistochemical and molecular features. The review is focused on follicular carcinoma, papillary carcinoma, follicular variant of papillary carcinoma, and oncocytic (Hürthle cell) tumors, as well as on the recently described borderline lesions: follicular and well-differentiated tumors of uncertain malignant potential, and well-differentiated carcinoma, not otherwise specified.     

TGF-B and Estrogen Regulate P27(Kip1) and Cyclin D(1) in Normal and Neoplastic Rat Pituitary Cells

Pituitary hyperplasia and tumor growth are regulated by various hormones and growth factors. Estrogen (E₂) stimulates pituitary cell proliferation and prolactin (PRL) production. Estrogen also regulates transforming growth factor-β (TGF-β) effects in the pituitary. TGF-β in turn regulates various cell cycle proteins including p15 and p27^Kip1 (p27). To better understand the regulatory role of growth factors and hormones in the cell cycle we analyzed cyclin D₁, cyclin E, and p27 expression in normal and neoplastic rat pituitary cells. An in vitro analysis using cultured normal pituitary cells and GH₃ tumor cells and an in vivo analysis of estrogen-treated normal pituitary and implanted GH₃ cells were performed. Semiquantitative RT-PCR was used to analyze mRNA expression for cyclin D₁, cyclin E, and p27 in cultured pituitary cells and E₂-treated pituitaries in vivo. Cyclin D₁ and p27 were localized in the nuclei of normal pituitary cells by immunocytochemistry (ICC). Very weak or absent immunostaining for cyclin D₁ and p27 was present in GH₃ cells. Both normal pituitary and GH₃ cells had strong nuclear staining for cyclin E. Normal pituitary had a 20-fold greater amount of cyclin D₁ mRNA and a 3-fold greater amount of p27 mRNA compared to GH₃ cells, whereas GH₃ cells had slightly (1.5-fold) more cyclin E than normal pituitary cells. E₂ treatment in vivo stimulated cell proliferation and decreased cyclin D₁ mRNA levels in normal pituitary. GH₃ tumor cells, implanted subcutaneously in the same animal, showed increased proliferation after E₂ treatment, but there was no change in cyclin D₁ mRNA in GH₃ cells. Cyclin E and p27 mRNA levels did not change significantly in normal pituitary or in GH₃ cells after E₂ treatment in vivo. Treatment of normal pituitary cells with 10⁻⁹ M TGF-β1 for 3 d in vitro led to significant decreases in cyclin D₁ and p27 mRNAs (p < 0.05), whereas cyclin E levels were unchanged. These results indicate that cyclin D₁ and p27 mRNAs are present at significantly higher levels in normal pituitary compared to GH₃ cells, and that both E₂ and TGF-β1 can downregulate cyclin D₁ mRNA levels in normal pituitary cells, suggesting that these factors regulate G1 to S phase transition in pituitary cells. The lower levels of specific cell cycle regulators in GH₃ cells may explain the decreased regulatory control by E₂ in GH₃ tumor cells.     

Differential expression of human telomerase catalytic subunit mRNA by In situ hybridization in pheochromocytomas

In pheochromocytomas, it is very difficult to predict malignant potential by conventional histology or immunohistochemical and molecular markers. We investigated the expression of human telomerase catalytic component (hTERT) mRNA, hTERT protein, Ki-67 antigen, and p27^kip1 in pheochromocytomas (27 benign, 7 suspected malignant, and 7 malignant), and evaluated the possibility of expressions of these proteins, and hTERT mRNA serve as diagnostic markers for predicting the biological behavior of these tumors. All tumors showed the classical histology and typical immunohistochemical pattern. By in situ hybridization, hTERT mRNA was expressed in 5/7 malignant tumors (defined as the presence of metastasis and/or extensive local invasion) as compared with 3/27 benign tumors. We examined the hTERT by immunohistochemistry to confirm the mRNA. hTERT mRNA expression was correlated with hTERT protein expression. All benign tumors exhibited no immunopositivity or <1% of cells stained for Ki-67 antigen. Six out of seven malignant tumors have shown either hTERT mRNA expression or Ki-67 immunoreactivity While no statistical difference in p27^kip1 expressions was observed among benign, malignant, and suspected malignant tumors, there was a statistical difference between the normal adrenal medulla samples and tumors (p<0.001). Thus, hTERT mRNA detection by in situ hybridization, hTERT expression, and Ki-67 antigen expression are all useful tools for differentiating malignant from benign pheochromocytomas.     

Expression of p21<Superscript>cip1</Superscript>, p27<Superscript>kip1</Superscript>, and p16<Superscript>INk4a</Superscript> Cyclin-Dependent Kinase Inhibitors in Papillary Thyroid Carcinoma: Correlation with Clinicopathological Factors

In a variety of human malignancies, aberrant expression of proteins involved in the control of cell-cycle progression has been reported. In this study, p21^cip1, p27^kip1, and p16^INk4a cyclin-dependent kinase inhibitors were analyzed to evaluate their usefulness in clinical management of papillary thyroid carcinoma (PTC). Archived material derived from 46 cases of PTC was analyzed immunohistochemically. Protein expression was ascertained on tissue microarrays, and results were correlated with clinicopathological features of the patients. Positive immunostaining was observed in 14 (30,4%) p21^cip1, 26 (56,5%) p27^kip1, and 14 (30,4%) p16^INk4a cases. No significant correlation between p21^cip1 or p27^kip1 and clinical factors was found. In contrast, p16^INk4a expression showed a significant correlation with initial extension of the disease. Therefore, 45.8% of patients with loco-regional extension were p16^INk4a positive, whereas overexpression was only seen in 15.7% of cases with intrathyroid disease (p < 0.05). Moreover, all patients with simultaneous p16^INk4a positivity and lack of p27^kip1 staining (four patients) presented lymph node metastases. In contrast, only 12 (28.5%) of the remaining patients showed lymph node tumor involvement. In conclusion, p16^INk4a expression suggests extrathyroid neck extension of PTC. This effect is enhanced when p27^kip1 is negative. We think that their analysis by immunohistochemistry could be useful in the management of patients with PTC.     

Mycophenolate mofetil and roscovitine decrease cyclin expression and increase p27(kip1) expression in anti Thy1 mesangial proliferative nephritis

The response of mesangial cells to a phlogistic challenge includes cell proliferation and mesangial matrix expansion. Cell proliferation is a highly regulated process which includes enhancing factors such as cyclins, cyclin dependent kinases, and inhibitory proteins, such as p27(kip1). The aim of the study was to evaluate the effects of Mycophenolate mofetil (MMF), and roscovitine (R), on the cell cycle regulatory system when administered in the florid phase of the experimental model of mesangial proliferative nephritis induced by the anti Thy-1 antigen monoclonal antibody. Three days after nephritis induction, different groups were given MMF and R. Rats treated with MMF or R showed a slight decrease in mesangial proliferation and matrix expansion. Samples of cortical tissue were tested by 'real time' RT-PCR in order to study gene expression of cyclins B, D1, D2, D3, E, and the cyclin inhibitor p27(kip1). Localization of mRNA was evaluated by in situ hybridization. Real time RT-PCR analysis showed a significant decrease in cyclins B, D1, D2, and D3 in rats treated with either MMF or R as compared to controls. Both MMF and R treatment induced a significant increase in p27(kip1) mRNA expression. In situ hybridization showed a mesangial-endothelial expression pattern in glomeruli. The number of labelled cells per glomerulus, the number of positive glomeruli in each examined slide as well as cyclin D2 and D3 signal intensity was significantly lower in rats treated with MMF or R as compared to controls, whereas MMF or R treatment up-regulated p27(kip1) mRNA expression. Immunohistochemical evaluation of p27(kip1) aimed to examine the influence of MMF or R on protein expression confirmed up-regulation.     

Accumulation of p27(kip1) is associated with cyclin D3 overexpression in the oxyphilic (Hurthle cell) variant of follicular thyroid carcinoma

BACKGROUND: The down regulation of protein p27(kip1) (p27) in most cases of thyroid cancer has relevant diagnostic and prognostic implications. However, the oxyphilic (Hurthle cell) variant of follicular thyroid carcinoma expresses more p27 than benign oxyphilic lesions do. AIM: To evaluate the mechanism underlying this difference in expression of p27. METHODS: Because high levels of cyclin D3 lead to p27 accumulation in cell lines and clinical samples of thyroid cancer, the immunocytochemical pattern of cyclin D3 in oxyphilic (n = 47) and non-oxyphilic (n = 70) thyroid neoplasms was investigated. RESULTS: In the whole study sample, there was a significant correlation between p27 and cyclin D3 expression (Spearman's r: 0.64; p<0.001). The expression of cyclin D3 and p27 was significantly higher in the oxyphilic variant of follicular carcinomas than in non-oxyphilic carcinomas (p<0.001). In the former, cyclin D3 overexpression and p27 accumulation were observed in a median of 75% and 55% of cells, respectively. In co-immunoprecipitation experiments, the level of p27-bound cyclin D3 was much higher in oxyphilic neoplasias than in normal thyroids and other thyroid tumours. CONCLUSION: These results show that increased p27 expression in the oxyphilic (Hurthle cell) variant of follicular thyroid carcinoma results from cyclin D3 overexpression.     

Mantle Cell Lymphomas Lack Expression of p27kip1, a Cyclin-Dependent Kinase Inhibitor

p27^Kip1 is a cyclin-dependent kinase inhibitor that regulates the decision to enter S phase or withdraw from the cell cycle. In resting cells, the level of p27^Kip1 provides an inhibitory threshold above which G1 cyclin D/E/cyclin-dependent kinases accumulate before activation; however, in cycling cells, p27^Kip1 protein is sequestered by high levels of active cyclin D/cyclin-dependent kinase 4 complexes. As a group, the cyclin-dependent kinase inhibitors have been proposed to act as tumor suppressor genes, and several members have been implicated in the pathogenesis of a variety of human cancers. We examined p27^Kip1 expression in 116 non-Hodgkin’s lymphomas including 50 cases of MCL (40 typical and 10 blastic variants), 21 follicular lymphomas, 20 diffuse large B-cell lymphomas, 16 chronic lymphocytic leukemias, 8 marginal zone B-cell lymphomas, and 1 splenic marginal zone lymphoma, and correlated its expression with that of the proliferation marker Ki67 (MiB1) and with p53. p27^Kip1gene structure was analyzed by Southern blot in the group of MCLs. In all cases of non-Hodgkin’s lymphoma other than MCL, p27^Kip1 expression was inversely related to the proliferation index as measured by Ki67. In contrast, in typical MCL, p27^Kip1 expression was negative in 35 of 40 (88%) cases, irrespective of the proliferative rate (median 15%; range 2 to 90%). Paradoxically, in the blastic variant of MCL, 8 of 10 (80%) cases showed expression of p27^Kip1, despite a high proliferation rate (median 60%; range 32 to 100%). However, the staining in most of the cases was less intense than in the reactive T lymphocytes. Deletions of p27^Kip1gene were not found in any of the 25 cases examined. p53 expression was found in 15 of 50 cases of MCL: 7 of 10 (70%) in the blastic variant and 8 of 40 (20%) in the typical MCL (70% vs. 20%, P < 0.0045). These results demonstrate that MCLs, in contrast to other non-Hodgkin’s lymphomas and normal lymphoid tissue, fail to correlate p27^Kip1 expression with the proliferation rate. This peculiar uncoupling of p27^Kip1 protein expression from the proliferation rate may be related to the high levels of cyclin D1 expressed in MCL and is likely to have profound effects on cell cycle regulation and contribute to the pathogenesis of MCL.     

Loss of p27kip1 expression is associated with poor prognosis in patients with taxane-treated breast cancer

Purpose

Decreased expression of p27^kip1 and p57^kip2 is considered as a prognostic indicator in patients with breast cancer receiving adjuvant chemotherapy. Previous in vitro studies have reported that reduced expression of p27^kip1 and p57^kip2 is associated with resistance to taxane, which is one of the most effective chemotherapeutic agents. In this study, we investigated the association of low p27^kip1 and p57^kip2 expression with outcomes in patients with breast cancer.

p27 Kip1 protein expression in Hashimoto's thyroiditis

AIMS: Hashimoto's thyroiditis (HT) is an autoimmune disease in which both proliferation and apoptosis are enhanced. p27(Kip1) protein protects tissues from disease mechanisms that involve excessive cell proliferation and apoptosis. This study investigated whether there is loss of p27(Kip1) expression in HT and whether p27(Kip1) immunoreactivity has any relation to the proliferative indicator Ki-67. Because p27(Kip1) is regulated through either degradation, mediated by the S phase kinase associated protein 2 (Skp2), or sequestration, via D3 cyclin, the expression of these proteins was also investigated. METHODS: Immunohistochemistry was used to assess p27(Kip1), Ki-67, Skp2, and cyclin D3 expression in 19 cases of HT and in 10 normal thyroids. The results were evaluated by image analysis and reported as labelling indices (LIs) in both groups. RESULTS: The p27(Kip1) LI was lower in HT than in normal thyroid (28% v 75%; p < 0.001), whereas Ki-67 (1.13% v 0.13%), Skp2 (0.74% v 0.15%), and cyclin D3 (1.56% v 0.00%) LIs were higher in HT than in normal thyroids (p < 0.001). There was no correlation between p27(Kip1) and the expression of Ki-67, Skp2, and cyclin D3. CONCLUSIONS: p27(Kip1) downregulation is not exclusive to tumours but occurs also in HT, independently of the proliferative status and of changes in Skp2 and cyclin D3 expression. Further investigation is required to understand the mechanisms leading to p27 deregulation because these observations suggest that the regulation of p27(Kip1) expression in epithelial thyroid cells may play a role in HT pathogenesis.     

Expression patterns of cyclins D1 and E in condyloma acuminatum in comparison with psoriatic proliferative lesions

Human papillomavirus (HPV) is able to subvert the host cell replication machinery so as to foster viral reproduction. Specifically, HPV infection is known to induce expression of proliferation antigens such as Ki67 and proliferative cell nuclear antigen (PCNA) in differentiated keratinocytes which have ceased to replicate. In order to determine whether cyclin D1 or cyclin E deregulation is also a feature of HPV infection, an immunohistochemical investigation of cyclin D1, cyclin E, Ki67, and PCNA expression has been carried out in 38 cases of HPV 6/11-related condyloma acuminatum (CA). Results were compared with those obtained from 15 psoriatic proliferative lesions. Whereas 35 (92·1 per cent) CA samples exhibited positive nuclear immunostaining for cyclin E, no cyclin D1 immunoreaction was detected in any of the CA samples studied. All psoriatic lesions showed immunostaining for both cyclins. All CA cases revealed a positive immunoreaction for Ki67 and 33 for PCNA, both in the parabasal and in the differentiated upper epithelial layers. Parabasal keratinocytes of psoriatic lesions were always positive for both Ki67 and PCNA. These results indicate that in the onslaught of HPV 6/11 upon the keratinocyte replication machinery, cyclin E, PCNA, and Ki67 are amongst the targeted cell cycle modulators, whereas cyclin D1 is spared the main effects of virus–cell interplay. In contrast, both cyclins seem to be induced in psoriasis, a non-viral proliferative skin condition. © 1998 John Wiley & Sons, Ltd.     

Expression of Ki-67 and p27(Kip1) in fine-needle aspirates from breast carcinoma and benign breast diseases

Cell atypia in breast fine needle aspiration (FNA) can introduce some diagnostic difficulties. Molecules reflecting proliferative cell potential, such as Ki‐67 and p27^Kip1, can help in recognizing the true biological nature of a cell. Thus, the objective of the study was to analyze the difference in Ki‐67 and p27^Kip1 cell immunoexpression in breast FNA specimens between fibroadenomas, fibrocystic changes (FCC) with atypia, and breast carcinoma. Microscopic analyses of cell cytomorphology and Ki‐67 and p27^Kip1 breast cell immunoexpression were done after standard Pappenheim and immunocytochemical staining (labeled streptavidin‐biotin, LSAB) method in autostainer DakoCytomation TechMate?. The study included 50 patients with breast carcinoma, 20 patients with fibroadenoma, and 20 patients with FCC with atypia. High Ki‐67 and low or absent p27^Kip1 were found in most patients with breast carcinoma, while majority of FCC with atypia were characterized by low Ki‐67 and moderate to high p27^Kip1 cell immunoexpression. Majority of fibroadenomas were associated with low Ki‐67 and low to moderate p27^Kip1 cell immunoexpression indicating progressive decrease in cell cycle inhibition, but still not so high proliferative activity as in carcinoma. However, although statistically significant difference for Ki‐67 and p27^Kip1 was found between breast lesions in our study, the large ranges observed for each marker make them essentially useless for better cytological diagnosis in a single case. Regarding their opposite role in cell cycle, inverse correlation of Ki‐67 and p27^Kip1 was noticed. Poorly differentiated carcinoma cells had mostly high Ki‐67 andlow p27^Kip1 cell immunoexpression. Diagn. Cytopathol. 2011;39:333–340. © 2010 Wiley‐Liss, Inc.