Correlation of Ki-67 and p53 with the new World Health Organization/International Society of Urological Pathology Classification System for Urothelial Neoplasia

OBJECTIVE: The present study examines p53 and Ki-67 staining patterns of the diagnostic entities included within the new World Health Organization/International Society of Urological Pathology (WHO/ISUP) classification of urothelial neoplasms. DESIGN: We retrospectively studied 151 bladder biopsies from 81 patients with the following neoplasms: normal urothelium (n = 34 biopsies); low-grade intraurothelial neoplasia (LGIUN; n = 19); high-grade intraurothelial neoplasia (HGIUN; n = 20); papillary hyperplasia (n = 4); papilloma (n = 3); papillary neoplasm of low malignant potential (LMP; n = 12); low-grade papillary carcinoma (n = 28); and high-grade papillary carcinoma (n = 31). Sections were labeled immunohistochemically with antibodies to p53 and Ki-67 (MIB-1). Two hundred cells from each lesion were visually counted, and the percentage of positive cells was tabulated without knowledge of the WHO/ISUP diagnosis. RESULTS: In flat lesions, p53 positivity was of limited diagnostic utility; the marker was present in 6 of 34 benign biopsies, 6 of 19 LGIUNs, and 10 of 20 HGIUNs. In one case in which HGIUN was present elsewhere in the bladder, 29% of the benign urothelial cells were p53 positive. In papillary lesions, p53 positivity was not seen in 4 of 4 cases of papillary hyperplasia, 3 of 3 papillomas, and 8 of 12 LMP tumors. In contrast, p53 was detected in 18 of 28 low-grade and 26 of 31 high-grade papillary urothelial carcinomas. A p53 labeling index (LI) greater than 30% was only seen in HGIUNs and high-grade papillary carcinomas. In flat lesions, an increased Ki-67 LI separated out benign urothelium (mean LI, 0.62%) from dysplasia (mean LI, 3.3%) and HGIUN (mean LI, 11.6%). In papillary lesions, Ki-67 positivity was as follows: papillary hyperplasia (mean LI, 1.1%); papilloma (mean LI, 4.3%); LMP tumors (mean LI, 2.5%), low-grade papillary carcinoma (mean LI, 7.3%); and high-grade carcinoma (mean LI, 15.7%). A Ki-67 LI greater than 10% was seen only in low- and high-grade papillary carcinomas, HGIUN, and single cases of LGIUN and papillary neoplasm of LMP. CONCLUSIONS: An increased proliferative index as demonstrated by immunohistochemical staining for Ki-67 (MIB-1) is most often seen in papillary carcinoma and HGIUN. Marked p53 positivity is also characteristic of carcinoma but may be seen in benign-appearing urothelium, suggesting a "field effect" with occult molecular aberration.     

Relationship of Ki67, TP53, MDM-2 and BCL-2 expressions with WHO 1973 and WHO/ISUP grades, tumor category and overall patient survival in urothelial tumors of the bladder

Using the 1998 World Health Organization/International Society of Urological Pathology (WHO/ISUP) (2004 WHO), 1999 WHO/ISUP, and 1973 WHO classifications, we examined Ki67, BCL-2, TP53, and MDM-2 expressions in invasive and noninvasive urothelial neoplasias of the bladder of 72 patients, and compared the results regarding tumor category and grade with clinical outcome to determine the clinicopathological relevance of these classifications. Ki67 and TP53 expressions were correlated with tumor grades of the 1973 WHO classification, and they also distinguished "papillary urothelial neoplasm with low malignant potential" from other WHO/ISUP grades (p < 0.05). No difference was observed for Ki67 and TP53 expressions between the other WHO/ISUP grades (p > 0.05). Neither tumor grade nor tumor category correlated with MDM-2 or BCL-2 expressions (p > 0.05). WHO/ISUP classifications are obviously not superior to the 1973 WHO classification for grading urothelial neoplasia of the bladder. However, if the "papillary urothelial neoplasm with low malignant potential" is distinguished from grade 1 tumors of the 1973 WHO classification, more precise prognostic information may be obtained.     

Relationship of cytokeratin 20 and CD44 protein expression with WHO/ISUP grade in pTa and pT1 papillary urothelial neoplasia.

The aim of this study was to assess the relationship of immunoreactivity of cytokeratin 20 (CK20) and CD44 across the spectrum of urothelial neoplasia using the WHO/ISUP consensus classification. A total of 120 papillary urothelial pTa and pT1 tumors (8 papillomas, 8 neoplasms of low malignant potential, and 42 low-grade and 62 high-grade carcinomas) were immunostained by using CK20 and CD44 antibodies. The relationships of tumor grade, pathologic stage, recurrences, and progression in stage with CK20 and CD44 immunoreactivity were assessed. WHO/ISUP grade correlated with tumor stage (P < 0.005), recurrence (P = 0.02), and progression in stage (P = 0.031). Normal urothelium showed CK20 immunoreactivity restricted to a few umbrella cells. Expression of CD44 in normal urothelium was restricted to the basal cell layer. Loss of CD44 immunoreactivity and increasing CK20 positivity were significantly associated with increasing tumor grade and stage (P < 0.005). An inverse relationship was observed in the staining patterns of CK20 and CD44 within individual cases, as well as in the aggregate data, with 79.2% of tumors with CD44 loss showing CK20 positivity (P < 0.001). In conclusion, CK20 and CD44 immunoreactivity are significantly related to the WHO/ISUP grade and to each other, and our data suggest their potential combined utility in predicting biologic behavior in patients with papillary urothelial pTa and pT1 neoplasms.     

卵巢低、高级别浆液性癌的临床病理分析及Pax2、p53和Ki-67表达的意义

目的 初步评估卵巢浆液性癌的两级分级系统在病理诊断和预后判断中的应用价值,探讨低、高级别浆液性癌Pax2、p53和Ki-67的表达及其与预后的相关性.方法 依照两级分级系统对卵巢浆液性癌进行分级,分别选取低级别癌38例,高级别癌100例,观察其临床病理特点,并采用免疫组织化学EnVision法检测癌组织中Pax2、p53和Ki-67的表达情况.结果 (1)低级别组的总生存时间、无病生存时间和5年生存率均显著优于高级别组(P＜0.05).(2)低级别组Pax2的阳性率显著高于高级别组(65.8%比13.0%,P＜0.05),而p53强阳性率显著低于高级别组(13.2%比55.0%,P＜0.05),Ki-67阳性指数显著低于高级别组(13.7%比42.1%,P＜0.05).(3)Pax2阳性组的总生存时间和5年生存率均显著优于阴性组(P＜0.05),而无病生存时间的差异无统计学意义(P＞0.05).p53和Ki-67阳性指数与生存时间的差异无统计学意义(P＞0.05).结论 两级分级系统对卵巢浆液性癌的预后判断有提示意义,在临床病理诊断中具有可行性.Pax2、p53和Ki-67在卵巢低、高级别浆液性癌中的表达差异有统计学意义.与p53和Ki-67相比,Pax2更有可能成为卵巢浆液性癌的一个预后相关指标.

Abstract：

Objective To evaluate the two-tier system for the grading of ovarian serous carcinomas,and to analyze Pax2, p53, Ki-67 protein expression and their prognostic values for low- and high-grade ovarian serous carcinomas. Methods A total of 38 cases of low-grade and 100 cases of high-grade ovarian serous carcinomas were selected based on the two-tier grading system. Innnunohistochemistry was used to detect Pax2, p53 and Ki-67 protein expression in all cases. Correlation of the two-tier system with immunohistochemical results and prognostic parameters were performed. Results ( 1 ) The overall survival,disease-free survival and 5-year survival rates were significantly higher in the low-grade serous carcinoma cases than in the high-grade cases ( P ＜ 0. 05 ). (2) Significant differences in protein expressions were found between the low- and high-grade serous carcinomas. The high-grade serous carcinomas had a significantly higher expression level of p53 (55.0% vs 13. 2%, P ＜ 0. 05 ) and Ki-67 (42. 1% vs 13.7%, P ＜ 0. 05 ),while low-grade carcinomas had a significantly higher expression level of Pax2 (65. 8% vs 13.0%,P ＜ 0. 05 ). (3) Pax2 positive cases had a significantly better overall survival and 5-year survival rates than Pax2 negative cases ( P ＜ 0. 05 ). The expressions of p53 and Ki-67 were found to have little correlation with overall survival and disease-free survival( P ＞ 0. 05 ). Conclusions The two-tier system for the grading of ovarian serous carcinomas has a good prognostic value. There are significantly differences in expressions of Pax2, p53 and Ki-67 between low- and high-grade ovarian serous carcinomas. Compared with p53 and Ki-67, Pax2 is likely a better prognostic indicator for ovarian serous carcinoma.     

Usefulness of endoscopic biopsy using immunostaining of p53 and Ki-67 in tumors of the ampulla of Vater

We investigated the diagnostic and prognostic value of p53 expression and proliferative activity, as indicated by the Ki-67, in endoscopic biopsy specimens. Specimens were immunologically stained with p53 and MIB-1 (Ki-67), and the MIB-1/Ki-67 labeling index (LI) was calculated. Classification of adenomas was based on findings of H&E-stained preparations into those with low- or high-grade atypia. Well-differentiated tubular and papillary adenocarcinomas were classified as carcinomas with low- or high-grade atypia. There were significant differences among the control and adenoma patients in MIB-1/Ki-67 LI (P < 0.05). No significant difference was identified between adenomas with high grade atypia and carcinomas with low grade atypia. The p53 expression was negative in all adenomas, but it was positive in 68.2% of carcinomas. The current study demonstrated that p53 protein expression in endoscopic biopsy specimens was of preoperative diagnostic value for carcinoma of the ampulla of Vater. The p53 protein positive tumors had a relatively higher malignant potential than p53 protein negative ones. The MIB-1/Ki-67 LI was useful in differentiating non-tumorous lesions from adenomas and adenomas with low- or high-grade atypia. The MIB-1/Ki-67 LI had a prognostic value because clinicopathological factors of carcinoma of ampulla of Vater correlated with MIB-1/Ki-67 LI.     

Prognostic markers in low-grade papillary urothelial neoplasms of the urinary bladder: an update

Papillary urothelial neoplasms of the urinary bladder comprise a heterogeneous spectrum of ‘continuous’ lesions in which the assessment of an accurate histological grade and tumour stage is mandatory for the clinical management of patients. The 1998 World Health Organization/International Society of Urologic Pathologists (WHO/ISUP) consensus classification and the 1999 WHO classification proposed new malignancy grading schemes, mainly based on morphometric studies for the replacement of the 1973 WHO grading system. In accordance with these novel grading systems, two major categories of papillary urothelial neoplasms were distinguished: low-grade and high-grade papillary urothelial neoplasms. Concerning the specific subgroup of low-grade tumours, two other entities were defined: papillary urothelial neoplasms of low malignant potential (PUNLMP) and low-grade papillary urothelial carcinomas (LGPUC). In long-term follow-up programmes, PUNLMP have demonstrated low recurrence rates and minimal risk for tumour progression in comparison with LGPUC. However, grade assessment is a subjective decision and, on occasion, the use of reproducible criteria by urological pathologists is difficult due to tumour heterogeneity and to the existence of a variable number of cases situated between consecutive groups. As a result, to determine a better correlation with clinicopathological patient outcome, other predictive markers are being investigated. Among these, the prognostic significance of classical clinicopathological, morphometric, cytometric, immunohistochemical and molecular markers have been widely reported. This review summarizes the prognostic importance of all these markers in the prediction of tumour recurrences and progression in low-grade papillary urothelial bladder neoplasms.     

Comparison of the WHO/ISUP classification and cytokeratin 20 expression in predicting the behavior of low-grade papillary urothelial tumors. World/Health Organization/Internattional Society of Urologic Pathology.

It has not been possible to identify those low-grade papillary transitional cell bladder tumors that will recur based on conventional histopathologic assessment. Both the new World Health Organization/International Society of Urologic Pathology (WHO/ISUP) classification of transitional cell papillary neoplasms and the pattern of tumor cytokeratin 20 (CK20) immunostaining have been suggested as means of improving prognostication in low-grade transitional cell tumors. Forty-nine low-grade, noninvasive papillary transitional cell tumors were identified for the period between 1984 and 1993. The recently described WHO/ISUP classification was applied, and the tumors were classified histologically as papilloma, papillary neoplasm of low malignant potential (LMP) or low-grade papillary carcinoma. After CK20 immunostaining, the expression pattern in the tumor was classified as normal (superficial) or abnormal. Of 49 tumors, 20 were classified as papillary neoplasms of LMP and five of these patients (25%) experienced a recurrence. Of 29 tumors classified as low-grade papillary carcinoma, 14 (48.2%) recurred. In 46 of 49 cases, the CK20 immunostaining could be evaluated. Sixteen tumors showed normal (superficial) pattern of CK20 expression, and four (25%) of these patients experienced a recurrence. In contrast, of 30 patients with abnormal CK20 staining of their tumors, 15 (50%) patients had one or more recurrences. In this study, papillary neoplasms of LMP (as per the WHO/ISUP classification system) had a lower recurrence rate than low-grade papillary transitional cell carcinoma. Similarly low-grade urothelial tumors showing a normal CK20 expression pattern recurred less frequently than tumors with an abnormal pattern of CK20 staining. Neither of these differences was statistically significant, and recurrences were observed in 20% of patients whose tumors were both classified as papillary neoplasms of LMP and showed normal CK20 immunostaining; thus they do not allow a change in our current management of patients with low-grade papillary urothelial tumors, with close follow-up for all patients.     

Prognostic significance of atypical papillary urothelial hyperplasia

Typical papillary hyperplasia, a recently recognized precursor lesion to low-grade papillary urothelial neoplasms, consists of undulating folds of cytologically benign urothelium. Well-developed, branching fibrovascular cores of a papillary neoplasm are not evident. We have noted lesions with the architectural pattern of papillary hyperplasia; however, the overlying urothelium demonstrated varying degrees of cytologic atypia. We identified 15 cases of atypical papillary hyperplasia (13 males, 2 females, age 55 to 92) with overlying urothelium showing cytologic atypia. Of these cases, 8 (53%) were received in consultation. Of the 15 cases, 8 exhibited overlying flat carcinoma in situ (CIS), 4 had overlying dysplasia, and 3 were transitional between papillary hyperplasia with atypia and the earliest lesions of papillary neoplasia. Of these cases, 5 patients had multiple specimens with atypical papillary hyperplasia (range, 2 to 8) over time. Concurrent to the diagnosis of atypical papillary hyperplasia, there were 25 different urothelial lesions: CIS (n = 11), papilloma (n = 1), papillary neoplasm of low malignant potential with CIS (n = 1), high-grade papillary urothelial carcinoma (n = 10; 3 with CIS), small-cell carcinoma (n = 1), and infiltrating urothelial carcinoma (n = 1). Of 11 patients with known prior history, 2 had 12 prior urothelial neoplasms (9 low-grade papillary neoplasms, 2 papillary urothelial neoplasms of low malignant potential, and 1 high-grade papillary cancer). Of 10 patients with atypical papillary hyperplasia and a minimum of 1 year of follow-up, 9 had 19 recurrences: CIS (n = 4), papilloma (n = 1), papillary neoplasm of low malignant potential (n = 1), infiltrating urothelial carcinoma (n = 3; 1 with CIS), and high-grade papillary urothelial carcinoma (n = 10; 5 with invasion and 2 with CIS). Whether the papillary hyperplasia had overlying CIS or dysplasia did not affect the correlation with urothelial neoplasms. Immunohistochemical analysis of p53 and Ki-67 expression in 8 cases demonstrated overexpression of p53 (n = 2; 1 with overlying dysplasia and 1 with overlying CIS), and Ki-67 (n = 5; 2 with overlying dysplasia and 3 with overlying CIS). Taken together, these results suggest that atypical papillary hyperplasia is most frequently associated with CIS and high-grade papillary cancer. In some cases, CIS or dysplasia may evolve into atypical papillary hyperplasia, with further progression to high-grade papillary cancer. This process may be analogous to papillary hyperplasia without cytologic atypia progressing to low-grade papillary urothelial neoplasms.     

Histological grading of papillary urothelial carcinoma of the bladder: prognostic value of the 1998 WHO/ISUP classification system and comparison with conventional grading systems

AIM: To test the prognostic value of the 1998 WHO/ISUP (World Health Organisation/International Society of Urologic Pathology) consensus classification system in Ta papillary urothelial neoplasms of the bladder. METHODS: The histological slides of 322 patients with a primary Ta tumour were classified according to the consensus classification system, and recurrence free survival (RFS) and progression free survival (PFS) were assessed for a mean follow up period of 79 months. In the same patient group, the RFS and PFS rates for the 1973 WHO grading system and a low grade/high grade system were analysed. RESULTS: Recurrent tumours were seen in all categories of the 1998 WHO/ISUP classification system and five year RFS was not significantly different between the groups (p = 0.12). The five year PFS showed a small but significant difference (p = 0.04) between papillary neoplasms of low malignant potential (PNLMP) and high grade papillary urothelial carcinomas (HGPUCs). In the 1973 WHO classification, no significant difference was found in RFS and PFS between the different grades. In the low grade/high grade classification PFS was significantly better for low grade tumours (p = 0.01). CONCLUSION: The prognostic value of the 1998 WHO/ISUP classification system is limited to predicting PFS, especially between PNLMP and HGPUC. The prognostic value of this system over other grading systems is questionable.     

Frequent FGFR3 mutations in urothelial papilloma

Activating point mutations in the FGFR3 gene occur frequently in low-grade and low-stage bladder carcinomas, whereas they are rare in high-grade carcinomas. This study investigates the incidence of FGFR3 mutations in 12 urothelial papillomas and 79 pTaG1 tumours which were regraded according to the 1998 WHO/ISUP classification system, resulting in 62 papillary urothelial neoplasms of low malignant potential (PUNs-LMP) and 17 low-grade papillary urothelial carcinomas (LG-PUCs). FGFR3 mutation analysis of 21 ovarian Brenner tumours was also performed. Seventy-seven cases were detected with a mutation in the FGFR3 gene. The mutations were exclusively found in bladder neoplasms. In urothelial papilloma, generally considered a benign lesion, 9/12 (75%) mutations were found. This report is the first to describe a genetic defect in urothelial papilloma. A comparable percentage of mutations was found in PUNs-LMP (85%) and LG-PUCs (88%). No mutations were found in matched normal DNA from bladder tumour patients. The mean follow-up was 5.78 years (range 0.21-17.60 years). Five patients developed high-grade papillary urothelial carcinoma from 2.5 to 12 years after first diagnosis. Two patients died of bladder cancer. The mean number of recurrences (recurrence rate) per year was 0.03, 0.21, and 0.46, respectively, for papilloma, PUN-LMP, and LG-PUC. Urothelial papilloma is a rare lesion with a benign natural behaviour compared with PUN-LMP and LG-PUC of the bladder, but from a molecular perspective, papillomas should be classified together with all well-differentiated urothelial neoplasms.     

Cytologic diagnosis of low-grade papillary urothelial neoplasms (low malignant potential and low-grade carcinoma) in the context of the 1998 WHO/ISUP classification

The 1998 World Health Organization/International Society of Urological Pathology (WHO/ISUP) classification of urothelial neoplasms introduced a category called papillary neoplasm of low malignant potential (LMP) and separated it from low-grade papillary urothelial carcinoma (LGPUC), which was thought to yield abnormal cells in cytology specimens. The objective of our study was to evaluate the effectiveness of urine cytology in diagnosing these lesions. Eighty-six paired transurethral surgical biopsy and corresponding urine cytology specimens representing the spectrum of urothelial papillary lesions were examined. Consensus diagnosis on each biopsy was made, and the distribution was as follows: 16 benign urothelium, 27 LMP, 28 LGPUC, and 15 high-grade papillary urothelial carcinoma (HGPUC). This was followed by a blinded independent review of the urine cytology specimens by three observers. Each cytology case was marked as negative, atypical, suspicious, or positive for malignant cells by using previously published cytologic criteria. When the negative and atypical diagnoses were grouped together as "benign" and the suspicious and malignant diagnoses as "malignant," the detection rate of "malignancy" of the lesions was as follows: LMP, 37%; LGPUC, 25%; and HGPUC, 53%. The false positive rate was 6%, and the positive predictive value (PPV) was 94%. Detection rates of cells that were at least "atypical" were as follows: LMP, 74%; LGPUC, 79%; and HGPUC, 100%. While most of the LMP and LGPUC cases yielded cells that were at least "atypical," there was no significant difference in the distribution of cytologic diagnoses for LMP and LGPUC cases (P > 0.05). Urine cytology in the context of the 1998 WHO/ISUP classification appears to be useful as a screening tool but does not appear to discriminate LMP effectively from LGPUC.     

Urothelial tumor of the urinary bladder: immunohistochemical features

Morphological and clinical characteristics of the urinary bladder cancers (UBC) are important diagnostics and prognostic criteria, however the possibilities of biopsy using/for prognosis of recidivation or efficiency of UBC treatment are limited. The most popular diagnostic and prognostic immunohistochemical markers are the regulators of cell cycle (P53, P21, Ki-67) and cytokeratins. In order to revealed immunohistochemical criteria, objectively reflected the malignancy of UBC, we studied the expression level of P53, proliferative index of Ki-67 and the malignant of UBC according to CK20 in the biopsy of 32 patients with superficial UBC. The immunohistochemical reaction with antibody to P53, CK20 and Ki-67 was carried out at paraffin slices. We detected differences of P53 expression levels at carcinomas with high and low malignancy rate. The expression levels of CK20 and the Ki-67 proliferative index were different between Ta and T1-T2 cancers (p = 0.006). Intensity of nuclear staining with P53 antibodies could be use for estimation of the UBC malignancy rate. Pathological type of CD20 expression and high percentage of Ki-67-positive staining nucleus are evidence of the invasive urothelial tumors. The using of P53, Ki-67 and CD20 could be recommended for pathohistological investigation of biopsy and surgical material of UBC to diagnostic objectification and prognosis of its clinical course.     

The WHO/ISUP 1998 and WHO 1999 systems for malignancy grading of bladder cancer. Scientific foundation and translation to one another and previous systems

Recently, two new classification systems for grading of urothelial neoplasms have been published. The objective of both was to avoid the overdiagnosis of cancer and to create better criteria for the grades. The WHO/ISUP classification of 1998 distinguishes papilloma, papillary urothelial neoplasm of low malignant potential (PUNLMP), low and high grade carcinomas, whereas the WHO 1999 system subdivides the high grade into grades II and III, and is otherwise identical. This note summarizes studies supporting the rationale of the two new systems, describes pattern recognition criteria for the grades, and highlights the homology between them.     

Reproducibility of the 1998 World Health Organization/International Society of Urologic Pathology classification of papillary urothelial neoplasms of the urinary bladder

Objectives This study assessed the diagnostic agreement and intra- and inter-observer reproducibility of the World Health Organization/International Society of Urologic Pathology Consensus Classification of Urothelial Neoplasms (1998 WHO/ISUP classification) and the 1973 WHO classification.Methods A teaching set with 5 slides of each papillary neoplasm of low malignant potential, low-grade papillary carcinoma, high-grade papillary carcinoma, and a guideline, as well as a study set of 30 slides containing ten cases of each category, were sent to participants. Six pathologists expert in urological pathology reviewed the 30 slides of non-invasive papillary urothelial tumors in the study set. Diagnostic accuracy and reproducibility were evaluated using intra- and inter-rater techniques (kappa statistic).Results A moderate to substantial intra- and inter-observer reproducibility was achieved for both the 1998 WHO/ISUP and 1973 WHO classification. The results of the two classification systems were not different statistically (P>0.05). Reproducibility was lower in low-grade tumors for both classifications.Conclusions The new proposed classification system for non-invasive urothelial neoplasms does not increase the reproducibility. There is still a need for uniformity in grading in order to compare the different studies and therapies and to provide more accurate information for management.     

Transitional cell tumours of the bladder: classification and diagnostic pitfalls

Two classifications of transitional cell tumours have been published since 1998. Both have sought to address the nomenclature of non-invasive papillary tumours, as the practice stemming from the 1973 WHO classification of labelling virtually all of these tumours as carcinomas was judged to be unsatisfactory. Both classifications introduced the term of ‘urothelial neoplasm of low malignant potential’. The 1998 WHO/ISUP considered that this replaced the 1973 WHO grade 1 carcinoma, and that grades 2 and 3 would then be subdivided into low and high grade, whereas the 1999 WHO retained the three grades of carcinoma. The classifications are therefore not equivalent and in the absence of prospective data on clinical outcome and reproducibility studies, it is difficult to recommend their adoption. The importance of clinical factors in assessing the risk of tumour recurrence and progression must be emphasized, and closer integration of pathological and other clinical data should lead to improvements in individual patient outcome. This should also be the case for patients with muscle invasive disease, since urothelial carcinomas have a propensity to differentiate along different pathways, most commonly squamous, but also glandular or neuroendocrine, and the type of differentiation may affect responses to therapy.     

Non-invasive papillary urothelial neoplasms: The 2004 WHO/ISUP classification system

The classification and grading of papillary urothelial neoplasms has been a long-standing subject of controversy. Previously, numerous diverse grading schemes for bladder tumor, including the 1973 World Health Organization (WHO) classification, existed whereby one of the major limitations was poor inter-observer reproducibility among pathologists. The WHO/International Society of Urological Pathology (ISUP) consensus classification system of urothelial neoplasms of the urinary bladder was developed in 1998 and was revised most recently in 2003 (published in 2004). Importantly, the current classification system provides detailed histological criteria for papillary urothelial lesions and allows for designation of a lesion (papillary urothelial neoplasm of low malignant potential) with a negligible risk of progression. Thus, the latest system is designed to be a universally acceptable one for bladder tumors that not only could be effectively used by pathologists, urologists, and oncologists, but also stratifies the tumors into prognostically significant categories. This article outlines the 2004 WHO/ISUP classification system regarding the specific histological criteria for non-invasive papillary urothelial neoplasms and the clinical significance of each category.     

Clinicopathologic study of 60 cases of urothelial neoplasms with inverted growth patterns: Reclassification by international consultation on urologic disease (ICUD) recommendations

BackgroundMost urothelial neoplasms of the bladder show an exophytic papillary pattern, but some show an inverted growth pattern. In 2004, the World Health Organization (WHO) released a detailed histologic classification system for papillary urothelial neoplasms, but not for inverted forms. The International Consultation on Urologic Disease (ICUD) recommendations of 2012 are applicable to inverted/endophytic papillary lesions as follows: 1) inverted papilloma (IP), 2) inverted papillary urothelial neoplasm of low malignant potential (IPUNLMP), 3) inverted papillary urothelial carcinoma, low grade, non-invasive (IPUCLG-NI), 4) inverted papillary urothelial carcinoma, high grade, non-invasive (IPUCHG-NI), 5) inverted papillary urothelial carcinoma, high grade, invasive (IPUCHG-I). However, only atypical cellular morphology was considered for classification in the 2012 ICUD recommendations, and data to support to validate this new grading system are lacking.MethodsSixty cases of inverted urothelial papillary tumors were classified into 5 categories according to 2012 ICUD and 2016 WHO/ISUP recommendations to evaluate their clinical, pathological, and immunohistochemical characteristics. Two subgroups were defined as subgroup 1, IP and IPUNLMP, and subgroup 2, IPUCLG-NI, IPUCHG-NI, and IPUCHG-I. Clinical features (age, sex, history of urothelial carcinoma, smoking history, size, and multifocality) and histologic features (nuclear pleomorphism, mitotic count, mitosis level, apoptosis, luminal necrosis, trabecular thickening, anastomosing trabeculae, hypercellularity, loss of polarity, peripheral palisading, palisading with central streaming, and discohesiveness) were evaluated. Immunohistochemical stains for CK20, CD44, P53, p16, Ki-67, cyclin D1 and c-erbB2 were performed.ResultsA total of 60 cases were classified as 10 cases of IP, 29 cases of IPUNLMPs, 15 cases of IPUCLG-NI, 4 cases of IPUCHG-NI, and 2 cases of IPUCHG-I. Compared to subgroup 1, subgroup 2 showed larger tumor size, more nuclear irregularity, higher mitotic count (hot spot and per 10 high power fields), more upper level mitosis (>1/2), and more frequent apoptosis, luminal necrosis, surface papillary component, trabecular thickening, anastomosing irregular trabeculae, hypercellularity, loss of polarity, peripheral palisading with central streaming, and discohesiveness, and absence of umbrella cells and urothelial eddies. CK20, Ki67, and c-erbB2 were the only markers that were differently expressed in the two subgroups, with more expression in subgroup 2.ConclusionsThe 2012 ICUD recommendations are valid to classify inverted papillary urothelial tumors. However, other histologic features besides atypical cellular morphology should also be considered to distinguish subgroup 1 and subgroup 2 inverted papillary urothelial tumors.     

CK19、CK20在甲状腺乳头状癌诊断中的应用价值

目的：探讨甲状腺癌中CK19、CK20蛋白的表达，提高甲状腺的诊断与鉴别诊断水平。方法：应用免疫组化染色对70例甲状腺癌（15例经典型乳头状癌、34例滤泡型乳头状癌、3例Warthin乳头状癌、2例透明细胞型乳头状癌、例柱状细胞型乳头癌、15例滤泡性癌），10例甲状腺腺瘤、10例结节性甲状腺肿和5例标本甲状腺炎中CK19、CK20的表达进行观察。结果:CK19在甲状腺疾病中的表达：55例乳头状癌中，53例为中、强阳性，2例为弱阳性；15例滤泡性癌中，13例为阴性、弱阳性，2例为中、强阳性，两者之间差异存在显著性（P＜0．05）。各癌旁滤泡、10例滤泡性腺瘤、10例结节性甲状腺肿的滤泡、5例桥本甲状腺炎也主要为阴性、弱阳性，个别为中等阳性。对CK20的表达，各型甲状腺乳头状癌、滤泡性癌、癌旁滤泡及滤泡状癌和乳头状增生、多灶性分布的甲状腺泡型乳头状癌和各种滤泡性病变有帮助，可提高甲状腺良恶性病变诊断的准确率及鉴别诊断水平。CK20对鉴别诊断的帮助不大。     

p53, ki-67, galectin-3, HBME-1, 34βE12和CK19在甲状腺乳头状癌中的表达及临床病理意义

 摘要：目的：探讨p53, ki-67, galectin-3, HBME-1, 34βE12和CK-19在甲状腺乳头状癌中的表达及临床病理意义。方法：采用免疫组化检测43例甲状腺乳头状癌、37例结节性甲状腺肿、33例甲状腺腺瘤和17例桥本甲状腺炎中p53, ki-67, galectin-3, HBME-1, 34βE12和CK-19的表达。结果：p53, ki-67, galectin-3, HBME-1, 34βE12和CK-19在甲状腺乳头状癌中的阳性表达例数分别为88.37%、79.07%、88.37%、93.02%、86.05%、95.35%;6种蛋白在甲状腺乳头状癌与结节性甲状腺肿、甲状腺腺瘤和桥本甲状腺炎中的阳性表达率相比较差异均有统计学意义（P<0.01）。结论：联合检测p53, ki-67, galectin-3, HBME-1, 34βE12和CK-19在甲状腺乳头状癌与良性病变的诊断和鉴别诊断中具有重要的价值。     

乳腺导管内乳头状肿瘤187例临床病理及免疫组织化学特征

目的 探讨乳腺导管内乳头状肿瘤(IDPN)的诊断方法和标准.方法 收集187例IDPN患者的临床和病理资料,结合目前认可的2003年WHO乳腺和女性生殖系统肿瘤病理学和遗传学分类标准、Page等和Tavassoli的诊断标准,对其形态学特点进行分析,并对其中53例行CD10、p63、CK14、CK5/6、CK7、乳珠蛋白-1(MGB1)及p53免疫组织化学EnVision法染色分析.结果 187例IDPN患者中导管内乳头状瘤(IDPMa) 128例,不典型导管内乳头状瘤(A-IDPMa) 16例,导管内乳头状癌(IDPCa) 43例.IDPN在形态学上表现为不同程度的上皮细胞和间质增生,以及继发病变等,这些使病灶呈现异常复杂的多样性.免疫组织化学肌上皮标记(CD10和p63)染色在IDPMa、A-IDPMa及IDPCa的表达依次减少,组间比较差异均有统计学意义(均P＜0.001).基底型角蛋白(CK5/6和CK14)染色显示良性病变的表达呈镶嵌状阳性表达,在A-IDPMa的不典型区和IDPCa中表达明显减少或缺如,两者相比差异有统计学意义(P＜0.001).腺腔上皮标志物CK7染色各组间比较差异无统计学意义(P=0.06).MGB1在IDPCa组染色明显减少(P值分别为0.002和0.007),p53染色各组均呈阴性.结论 IDPN是一组组织学改变复杂的疾病,应注意其诊断标准的掌握.肌上皮、基底型角蛋白和腺腔上皮标志物联合应用在该组复杂病变中有很好的诊断和鉴别诊断价值.