Histological classification and stage of newly diagnosed bladder cancer in a population-based study from the Northeastern United States

OBJECTIVE: There are limited data on the distribution of bladder cancers in the general population, classified by World Health Organization (WHO)/International Society of Urological Pathology (ISUP) criteria. This study evaluated the classification and stage of bladder cancers as part of a population-based epidemiological study of bladder cancer in the Northeastern United States. MATERIAL AND METHODS: All New Hampshire residents with bladder cancer newly diagnosed from 1998 to 2000 were identified through the state cancer registry. All slides were reviewed by a single pathologist. Tumors were classified by two sets of standard criteria. RESULTS: The retrieval rate for cases was over 90%. Of 342 cases reviewed, 15 were excluded for technical reasons or because malignancy was not definitively diagnosed. According to WHO/ISUP criteria, 25.7% of tumors were papillary urothelial neoplasms of low malignant potential (PUNLMP), 34.3% low-grade papillary carcinomas, 22.6% high-grade papillary carcinomas, 10.1% non-papillary urothelial carcinomas and 5.5% carcinoma in situ. By WHO (1973) criteria, 52.5% of tumors were grade 1, 21.4% grade 2 and 26.1% grade 3. Two-thirds of all tumors were stage Ta, 20.8% stage T1 and 7.6% stage >or=T2. 100% of PUNLMPs were non-invasive, 6.3% of low-grade carcinomas were invasive and 64.9% of high-grade carcinomas were invasive. CONCLUSIONS: Compared to clinic or hospital referral-based series, this study documents a higher percentage of non-invasive tumors and a lower percentage of muscle-invasive tumors. There was also a higher percentage of PUNLMP tumors and fewer high-grade papillary carcinomas than in other series. These results may more accurately reflect prevalence data for bladder cancer grade and stage, although geographic variability may exist.     

Prognostic significance in substaging ofT1 urinary bladder urothelial carcinoma on transurethral resection

T1 papillary urothelial carcinomas of the urinary bladder run a variable clinical course, and an effective substaging system has not been defined yet. This study was conducted to devise an easy-to-use substaging method and to validate its prognostic value in T1 cancer on transurethral resection specimens. A total of 103 cases of T1 low-grade papillary urothelial carcinoma and 406 cases of T1 high-grade papillary urothelial carcinoma from a series of 1515 non-muscle-invasive bladder tumors treated by transurethral resection were studied. Substaging was performed using 0.5, 1.0, and 1.5 mm as thresholds to distinguish extensive from focal invasion. Correlations to recurrence, progression, cancer-specific mortality, and all-cause mortality were explored and compared with Ta tumors. All lamina propria invasions in low-grade papillary urothelial carcinomas were confined to 1.0 mm. The proportions of T1 high-grade papillary urothelial carcinoma invading beyond 0.5, 1.0 (T1>1 mm), and 1.5 mm were 53%, 32%, and 27%, respectively. No prognostic differences were found between Ta and T1 low-grade papillary urothelial carcinomas. T1>1 mm high-grade papillary urothelial carcinomas were associated with significantly greater risks for recurrence, progression, cancer-specific mortality, and all-cause mortality compared with T1≤1 mm and Ta tumors. Comparable statistical results could be obtained using 0.5 and 1.5 mm as cutoff points, but we recommend using 1.0 mm for practical consideration. Taking all non-muscle-invasive urothelial neoplasms of the bladder into consideration, 5 prognostically distinct categories can be established: (1) papillary urothelial neoplasms of low malignant potential; (2) low-grade papillary urothelial carcinoma Ta/1; (3) high-grade papillary urothelial carcinoma Ta; (4) high-grade papillary urothelial carcinoma T1≤1 mm; and (5) high-grade papillary urothelial carcinoma T1>1 mm. Our study demonstrates that the substaging of T1 bladder cancer is feasible, based on the evaluation of transurethral resection specimens, and can provide more precise prognostic information to identify a subset of patients with a more unfavorable prognosis.     

Urothelkarzinom

Various study groups are working on the WHO classification of 2004 which eliminates the previous grades of differentiation G1, G2, and G3 and classifies non-muscle-invasive bladder cancer into genetically stable low-grade and genetically unstable high-grade urothelial carcinomas. In muscle-invasive bladder cancer, extended lymph node dissection as part of radical cystectomy should remain the standard procedure for now.     

Urothelial carcinoma

Various study groups are working on the WHO classification of 2004 which eliminates the previous grades of differentiation G1, G2, and G3 and classifies non-muscle-invasive bladder cancer into genetically stable low-grade and genetically unstable high-grade urothelial carcinomas. In muscle-invasive bladder cancer, extended lymph node dissection as part of radical cystectomy should remain the standard procedure for now.     

非浸润性膀胱尿路上皮癌不同病理分级方法的临床应用价值比较

目的 比较非浸润性膀胱尿路上皮癌WHO 2004年和1973年病理分级方法的临床应用价值.方法 采用WHO 2004和1973 2种病理分级方法对160例非浸润性膀胱尿路上皮癌患者进行病理分级,随访患者复发和进展情况,比较分析2种分级系统临床应用差异. 结果 160例患者按1973分级方法:乳头状瘤5例,尿路上皮癌G_1 52例、G_2 83例、G_3 20例;按2004分级法:乳头状瘤7例,低度恶性潜能尿路上皮乳头状瘤(PUNLMP)31例、低分级尿路上皮乳头状癌(LGPUC)99例、高分级尿路上皮乳头状癌(HGPUC)23例.1973分级法各级别间复发与进展情况差异均无统计学意义(P>0.05);2004分级法各级别间复发差异无统计学意义(P>0.05),进展情况差异有统计学意义(P<0.05),其中PUNLMP与HGPUC差异有统计学意义(P<0.01).2004分级法HGPUC级别进展率(30.4%)明显高于1973分级法G_3级别进展率(15.0%). 结论 WHO 2004分级法中HGPUC级别衍含更多的高度恶性尿路上皮细胞癌,较1973分级法G_3级别更容易发生进展,临床上对HGPUC级别患者应采用更严密的治疗和随访措施.     

Significance of denuded urothelium in papillary urothelial lesions

Flat urothelial carcinoma in situ (CIS) is often characterized by prominent dyscohesion with some cases having only a few clinging CIS cells remaining on biopsy. The finding of extensive denudation on urothelial biopsies is associated with a risk of CIS on either prior or subsequent biopsies. The significance of denudation in papillary urothelial lesions has not been formally studied. We identified from our surgical pathology files 31 specimens (from 28 patients) of papillary urothelial lesions with extensive denudation. In cases in which denudation was associated with low-grade urothelial neoplasms, follow-up of subsequent cytologic and histologic specimens was obtained. Of the 28 patients, 25 (89%) were men and 3 (11%) were women with an age range of 40 to 88 years old (mean age 62). Of 31 biopsies, 15 were from anatomically confined areas (ie, renal pelvis, ureter, and urethra). In 22/28 (79%) patients, prominent denudation was associated with high-grade papillary carcinomas, 4/28 (14%) low-grade papillary carcinomas, and 2/28 (7%) papillary urothelial neoplasms of low-grade malignant potential. The average extent of urothelial denudation was 82% with 61% of cases having > or =90% denudation. Prominent cautery artifact was present in 17/31 (55%) cases. In 13/28 patients with high-grade lesions, there was a concurrent biopsy of a second urothelial lesion that was either high-grade papillary urothelial carcinoma or invasive urothelial carcinoma. Five of the 6 patients in which the prominent denudation was associated with a low-grade papillary urothelial lesion have not progressed to a high-grade lesion. One patient with a denuded papillary urothelial neoplasm of low malignant neoplasm was subsequently diagnosed with a noninvasive low-grade papillary urothelial carcinoma in the bladder and a high-grade infiltrating urothelial carcinoma of the ureter. We conclude that (1) the majority of papillary urothelial lesions associated with prominent urothelial denudation are high grade; (2) a significant percentage of papillary urothelial lesions with denudation occur with either prominent cautery artifact or in anatomically confined areas, suggesting both iatrogenic and mechanical contributing factors, respectively; (3) a minority of cases with prominent urothelial denudation occur in association with low-grade papillary urothelial lesions and are not associated with progression to higher grade lesions on follow-up studies; and (4) prominent urothelial denudation in papillary lesions should prompt careful examination of these specimens for rare clinging high-grade carcinoma cells, although in a minority of cases the underlying lesion will be low grade.     

Carcinoma of the parotid gland

BACKGROUND: The low incidence and heterogeneity of histiotypes of primary parotid carcinomas makes these tumors histologically and epidemiologically difficult to evaluate. The present study reviews a single institution's experience in the treatment of primary parotid carcinomas during the last 10 years. METHODS: The charts of 98 consecutive patients who had a primary parotid carcinoma and who received primary curative treatment were analyzed retrospectively. The tumors were grouped into high-grade and low-grade malignancies. The effect of treatment modalities on locoregional control, the incidence of locoregional recurrences and distant metastases, and survival rates are evaluated and compared between high- and low-grade malignancies. RESULTS: High- and low-grade malignant tumors were observed in 50 and 48 cases, respectively. Lymph node metastases were detected in 25 of 98 (25%) patients, of whom 8 of 22 (22%) clinically NO staged patients underwent elective neck dissection. In 24 of 26 resected facial nerves, a histologic tumor infiltration was confirmed, in 14 high-grade and 10 low-grade tumors. Local recurrence developed in 13 patients and was associated in 7 with high-grade and in 6 with low-grade tumors. All but 1 of the low-grade malignancies with local recurrence did not receive postoperative irradiation. Regional recurrence developed in 11 patients and distant metastases developed in 10, 3 in combination with a neck recurrence and 1 with a local recurrence. The survival rate at 5 years for low- and high-grade carcinomas was 87% and 56% and the disease-free survival rate 72% and 48%, respectively. CONCLUSIONS: The incidence of occult metastases in clinically N0-elective neck dissection was 22%. A routine elective neck dissection in all N0 parotid carcinomas is suggested. There is no statistically significant difference between low- and high-grade tumors as for the rate of local recurrence and, as all except one of the low-grade malignancies with local recurrence did not receive postoperative irradiation, postoperative irradiation is not only suggested for high-grade carcinomas but also for T2 to T4 low-grade carcinomas.     

Prognostic significance of a grading system considering tumor heterogeneity in muscle-invasive urothelial carcinoma of the urinary bladder

The fact that urothelial carcinomas (UC) often contain areas with different histologic grades has been recently shown to bear some prognostic relevance. Here we examined the prognostic significance of a grading system considering tumor heterogeneity in muscle-invasive bladder carcinomas. 151 UC treated by radical cystectomy were included. According to the World Health Organization/International Society of Urological Pathology (WHO/ISUP) classification, histologic grade was low-grade (LG) in 8 and high-grade (HG) in 143 cases. 65 HG tumors which focally harbored LG areas were assigned to mixed-type (MT) carcinomas. Mean follow-up was 50 months. While the WHO/ISUP classification showed no significant correlation with disease-specific survival (p = 0.3995 by log-rank test), stratification into LG/MT and HG tumors had a significant prognostic relevance (p = 0.0404). Nodal status was identified as the only independent prognostic factor (p = 0.0001 by multivariate analysis). In this respect, stratification into LG/MT and HG tumors missed the level of statistical significance by a norrow margin (p = 0.07 by multivariate analysis), but it turned out better than tumor category (p = 0.08). In conclusion, a grading system considering tumor heterogeneity may improve the predictive power of the WHO/ISUP classification in muscle-invasive UC of the urinary bladder. Although the two-tired grading system proposed in this study was not identified as an independent prognostic factor, it may help to obtain additional prognostic information on patients with advanced bladder cancer treated by radical cystectomy.     

膀胱低度恶性潜能乳头状尿路上皮肿瘤的复发进展因素分析

目的探讨膀胱低度恶性潜能乳头状尿路上皮肿瘤(papillary urothelial neoplasms of low malignant potential,PUNLMP)的病理特点及复发进展因素。方法回顾性分析空军军医大学第一附属医院2009年2月至2019年2月收治的150例膀胱PUNLMP患者的病例资料。男118例,女32例。年龄57(20~93)岁。单发肿瘤112例,多发肿瘤38例。所有患者均行经尿道膀胱肿瘤切除术(transurethral resection of the bladder tumor,TURBT),术后136例行膀胱灌注化疗(吡柔比星方案61例、吉西他滨方案58例、表柔比星方案11例、丝裂霉素方案11例),14例未行膀胱灌注化疗。采用单因素和多因素logistic回归分析确定膀胱PUNLMP患者TURBT术后复发、病理进展的独立预测因素。结果本研究150例术后随访25.6(5.5~122.7)个月,21例复发(复发组),复发时间为23.1(2.2~108.3)个月;12例病理进展(进展组),分别进展为低级别非浸润性乳头状尿路上皮癌9例,高级别非浸润性乳头状尿路上皮癌1例,高级别浸润性尿路上皮癌1例,鳞癌1例,进展时间为21.5(2.2~56.3)个月。150例中,18例病理检查提示伴有内翻性生长模式的患者均未复发。复发组初发肿瘤数量1、2、≥3个者分别为7、4、10例,未复发组(129例)分别为105、10、14例,差异有统计学意义(P<0.05)。复发组和未复发组肿瘤长径分别为2.0(1.0~3.8)cm和1.6(0.3~5.0)cm,差异有统计学意义(P=0.040)。进展组初发肿瘤数量1、2、≥3个者分别为4、3、5例,未进展组(138例)分别为108、11、19例,差异有统计学意义(P=0.003)。进展组和未进展组肿瘤长径分别为2.3(1.0~3.8)cm和1.7(0.3~5.0)cm,差异有统计学意义(P=0.046)。单因素和多因素分析结果显示,肿瘤数量是膀胱PUNLMP患者TURBT术后肿瘤复发(OR=7.884,95%CI 2.815~22.082,P<0.05)和进展(OR=6.107,95%CI 1.659~22.473,P=0.006)的独立预测因素,而膀胱灌注化疗与术后复发(OR=1.026,95%CI 0.213~4.950,P=0.974)和进展(OR=2.100,95%CI 0.412~10.713,P=0.372)无相关性。结论膀胱PUNLMP患者TURBT术后肿瘤复发率约14%,其中约50%的患者发生病理进展,多进展为低级别非浸润性乳头状尿路上皮癌。初发肿瘤为多发是膀胱PUNLMP患者术后复发和进展的独立危险因素。膀胱灌注化疗不能降低膀胱PUNLMP患者复发和进展风险。     

Neuerungen in der histologischen WHO-Klassifikation urothelial Harnblasentumoren und abnormer flacher Urothelläsionen

Recently the World Health Organization published a new classification of urinary bladder tumors which is intended to take into account better the biology of the various lesions and to better distinguish between clearly benign and malignant lesions.We examine the possible diagnostic and clinical impact of the new classification, including recent immunohistochemical findings.Papillary urothelial lesions include papillomas, papillary neoplasms of low malignant potential, and papillary carcinomas. Flat urothelial lesions include hyperplasia, reactive atypia/atypia of unknown significance, dysplasia, and carcinoma in situ. Invasive patterns of papillary carcinomas are discussed, with special emphasis on lamina muscularis mucosae substaging.The most important feature of the new classification is its differentiation of two types of low-grade, noninvasive papillary urothelial lesions: papillary neoplasm of low malignant potential vs. papillary carcinoma. Long-term follow-up studies are needed to determine the clinical significance of this differentiation.     

Urachal carcinomas of the nonglandular type: salient features and considerations in pathologic diagnosis

The vast majority of malignant urachal epithelial tumors have a glandular morphology (ie, adenocarcinoma), to which our principal understanding of urachal carcinoma and its prevailing set of diagnostic criteria are largely ascribed. The 2004 World Health Organization classification of genitourinary tumors recognizes other rarer histologic types of urachal carcinomas such as urothelial, squamous cell, and other carcinomas. However, the clinicopathologic data for these nonglandular groups of urachal carcinomas are very limited, being detailed only in sporadic case reports. Some of the criteria recommended for pathologic confirmation of urachal carcinomas were formulated almost exclusively for urachal adenocarcinoma and may not be relevant or applicable for nonglandular tumors. Here, we present 7 examples of pure (5) and mixed predominant (2) nonglandular urachal carcinomas. Patients were 45 to 85 years of age (mean, 64.1) with a male predominance (male-to-female ratio=6:1). Six tumors were related to the bladder [dome (3) or dome/supravesical (3)] and 1 was entirely supravesical. Histologically, 5 were urothelial carcinomas, of pure or mixed histology, all were high grade and invasive, and 2 were small cell carcinomas. Two urothelial carcinomas had focal (<5%) glandular differentiation and signet ring cell change, and 1 had admixed focal malignant squamous cells and high-grade dedifferentiated components. Four of 5 urachal urothelial carcinomas exhibited solid and partly cavitary or luminal growth with papillary structures and a variable amount of necrosis within the cavity. The 2 small cell carcinomas were pure, had classic undifferentiated neuroendocrine histology, were situated at the bladder dome, and were partly cavitary filled with necrotic debris. Urachal remnant was identified in 6 tumors mainly with dysplastic transitional cells in the urachal canal or rudimentary nests and tubules. All 6 bladder-related urachal tumors exhibited reverse invasive front from the surface, including 2 tumors that ulcerated the bladder mucosa. One tumor had concomitant in situ and noninvasive high-grade papillary urothelial carcinomas in the main bladder lumen. Sheldon stages at presentation were IIIA (2), IVA (3), and IVB (2). Follow-up in all 7 cases (<1 to 60 mo; median, 12.5 mo) showed that 6 patients had died of disease, including the 2 patients with small cell carcinoma. In conclusion, nonglandular urachal carcinoma may occur with pure histology or admixed with high-grade dedifferentiated morphologies and a minor adenocarcinoma component. These tumors may arise as deep-seated bladder-related or completely supravesical tumors along the urachal tract and may exhibit reverse invasive spread toward the bladder surface. Cavitary or luminal growth may occur that could be attributed to the intraurachal neoplastic proliferation. Urachal urothelial carcinomas in particular may contain papillary structures within the tumor and urachal cavity. Concomitant primary urothelial carcinoma outside of the urachus and tumor extension to bladder mucosa may occur, which should not negate diagnosis of an urachal primary. Behavior appears poor, as most tumors present with higher stage.     

The Emerging Molecular Landscape of Urothelial Carcinoma

Although there have been many recent discoveries in the molecular alterations associated with urothelial carcinoma, current understanding of this disease lags behind many other malignancies. Historically, a two-pathway model had been applied to distinguish low- and high-grade urothelial carcinoma, although significant overlap and increasing complexity of molecular alterations has been recently described. In many cases, mutations in HRAS and FGFR3 that affect the MAPK and PI3K pathways seem to be associated with noninvasive low-grade papillary tumors, whereas mutations in TP53 and RB that affect the G1-S transition of the cell cycle are associated with high-grade in situ and invasive carcinoma. However, recent large-scale analyses have identified overlap in these pathways relative to morphology, and in addition, many other variants in a wide variety of oncogenes and tumor-suppressor genes have been identified. New technologies including next-generation sequencing have enabled more detailed analysis of urothelial carcinoma, and several groups have proposed molecular classification systems based on these data, although consensus is elusive. This article reviews the current understanding of alterations affecting oncogenes and tumor-suppressor genes associated with urothelial carcinoma, and their application in the context of morphology and classification schema.     

The development of high-grade serous carcinoma from atypical proliferative (borderline) serous tumors and low-grade micropapillary serous carcinoma: a morphologic and molecular genetic analysis

Recently, we have proposed a model for the development of ovarian surface epithelial tumors. In this model, all histologic types of surface epithelial tumors are divided into 2 categories designated type I and type II which correspond to 2 pathways of tumorigenesis. Type I tumors include low-grade serous carcinoma, mucinous carcinoma, endometrioid carcinoma, malignant Brenner tumor, and clear cell carcinoma which develop slowly in a stepwise fashion from well-recognized precursors, namely atypical proliferative (borderline) tumors. Type II tumors are high-grade, rapidly growing tumors that typically have spread beyond the ovaries at presentation. They include high-grade serous carcinoma ("moderately" and "poorly" differentiated), malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinoma. These tumors are rarely associated with morphologically recognizable precursor lesions and it has been proposed that they develop "de novo" from ovarian inclusion cysts. This model implies that the pathogenesis of type I and type II tumors are separate and independent but it is not clear whether some type II tumors develop from type I tumors. In this study, we attempted to address this issue by determining the clonality of 6 cases of high-grade serous carcinomas that were closely associated with atypical proliferative serous (borderline) tumors and invasive low-grade micropapillary serous carcinomas. We reviewed 210 ovarian serous tumors from the surgical pathology files of the Johns Hopkins Hospital and identified 3 high-grade serous carcinoma that were directly associated with atypical proliferative serous (borderline) tumors and 3 that were associated with invasive low-grade micropapillary serous carcinomas. A morphologic continuum between the high-grade carcinoma and the low-grade tumors was observed in 4 cases whereas in the remaining 2 cases the high-grade and low-grade components were separate. Mutational analyses for KRAS, BRAF, and p53 genes were performed on microdissected samples from the high-grade and low-grade tumor areas for each case. All 6 tumors demonstrated wild-type BRAF and p53 genes. Only 2 of the 6 cases were informative from a molecular genetic standpoint. In those 2 cases we found the same mutations of KRAS in both the atypical proliferative serous (borderline) tumor and the high-grade serous carcinoma component of the tumor, indicating a clonal relationship. The above results suggest that the majority of high-grade and low-grade carcinomas develop independently but in rare cases, a high-grade serous carcinoma may arise from an atypical proliferative serous (borderline) tumor.     

Thymic mucoepidermoid carcinomas: a clinicopathologic study of 10 cases and review of the literature

BACKGROUND: Primary thymic carcinomas are rare malignant neoplasms, of which at least 10 different histologic variants have been described. Among these variants, thymic mucoepidermoid carcinomas morphologically similar to the homonymous salivary gland counterparts are particularly unusual; only 9 cases for which clinicopathologic features were available have been reported. OBJECTIVE: To study the clinicopathologic features of primary thymic mucoepidermoid carcinoma in an effort to better define their histologic features and biologic behavior. DESIGN: The clinical and pathologic features of 10 cases of thymic mucoepidermoid carcinoma were reviewed and compared with those of previously reported cases. RESULTS: The patients ranged in age from 8 to 84 years (mean 49 years), with 6 men and 4 women. The initial manifestations included respiratory symptoms and weight loss. Some patients were asymptomatic. All tumors were located adjacent to residual benign thymic tissue, and 3 cases were associated with multilocular thymic cysts. Histologically, the tumors consisted of sheets, lobules and nests of squamous, mucinous and intermediate cells in densely fibrotic stroma. There were 8 low-grade cases and 2 high-grade cases. The 2 patients with high-grade tumors died 1 year after diagnosis, whereas all but 1 patient with low-grade tumors in which follow-up was available were found to be alive and well on follow-up examination. One patient with low-grade tumor but high-stage disease died after developing a local recurrence. Among the 9 cases reported in the literature, 4 cases resulted in fatal outcomes; 2 cases were high-stage disease and 2 were high-grade tumors. CONCLUSIONS: Thymic mucoepidermoid carcinomas are predominantly low-grade tumors, and may be associated with multilocular thymic cysts. Poor prognosis is related to high-grade histology and high-stage disease.     

Papillary urothelial neoplasm of low malignant potential: reliability of diagnosis and outcome

OBJECTIVE: To determine the ability of pathologists to reproducibly diagnose a newly defined lesion, i.e. the papillary urothelial neoplasm of low malignant potential (PUNLMP) using the published criteria, defined by the 1998 World Health Organisation/International Society of Urological Pathology (WHO/ISUP) classification system; in addition, debate remains about the clinical behaviour of these lesions, thus the rates of recurrence and progression of PUNLMP lesions were assessed and compared with low-grade papillary urothelial carcinomas (LG-PUC) and high-grade (HG-PUC) over a 10-year follow-up. PATIENTS AND METHODS: Forty-nine cases of superficial bladder cancer (G1-3 pTa) representing an initial diagnosis of transitional cell carcinoma made in 1990 were identified and re-graded using the 1998 WHO/ISUP classification by two pathologists. Inter-observer agreement was assessed using Cohen weighted kappa statistics. After re-classification the clinical follow-up was reviewed retrospectively, and episodes of recurrence and progression recorded. RESULTS: The inter-observer agreement was moderate, regardless of whether one (kappa 0.45) or two (kappa 0.60) pathologists were used to grade these lesions. Re-classification identified 12 PUNLMP, 28 LG-PUC and nine HG-PUC. PUNLMP lesions recurred in 25% (3/12) of cases; no progression was documented. Recurrence rates were 75% (21/28) and 67% (6/9) for LG- and HG-PUC, respectively, and progression rates were 4% (1/28) and 22% (2/9). CONCLUSION: The 1998 WHO/ISUP classification of urothelial neoplasms can be reproducibly applied by pathologists, with a moderate level of agreement. There is evidence that PUNLMP lesions have a more indolent clinical behaviour than urothelial carcinomas. However, the risk of recurrence and progression remains, and clinical monitoring of these patients is important.     

Potential utility of uroplakin III,thrombomodulin, high molecular weight cytokeratin,and cytokeratin 20 in noninvasive,invasive, and metastatic urothelial (transitional cell) carcinomas

The morphology of urothelial carcinomas, particularly when poorly differentiated or in metastatic sites, is not distinctive and overlaps significantly with other poorly differentiated nonurothelial carcinomas. Currently, there is no widely used single marker or panel of markers to confirm urothelial origin. We evaluated a panel consisting of antibodies to uroplakin III (UROIII), thrombomodulin (THR), high molecular weight cytokeratin (HMWCK), and cytokeratin 20 (CK20) in a wide range of urothelial tumors. Immunohistochemistry was performed on 112 paraffin-embedded urothelial neoplasms: 14 low malignant potential, 16 low-grade noninvasive, 16 high-grade noninvasive, 36 invasive, and 25 metastatic and 5 small cell carcinomas of the urinary bladder. Tissue microarray analysis was used to examine 498 tissue cores of nonurothelial tumors and normal tissue using antibodies to UROIII, THR, and HMWCK. Overall positive staining results in all urothelial tumors are as follows: UROIII, 64 of 112 (57.1%); THR, 77 of 112 (68.8%); HMWCK, 88 of 110 (80%); and CK20, 53 of 110 (48.2%). The expression of the four markers varied with tumor grade and stage. All small cell carcinomas were negative for all markers. Variant morphologic subtypes showed similar staining as conventional urothelial carcinomas. Tissue microarray analysis showed no UROIII immunoreactivity in tissue cores of nonurothelial tumors. THR was expressed by a limited number of nonurothelial cores (10 of 37 [27%] non-small cell lung carcinomas, 2 of 36 [5.6%] lymphomas). HMWCK was expressed by 43.8% of non-small cell lung carcinomas and essentially absent in other nonurothelial tumor cores. Based on the results of the study, the expression of UROIII in a tumor is essentially diagnostic of urothelial origin; however, it is expressed in only slightly more than half of urothelial tumors. The coexpression of THR, HMWCK, and CK20 strongly suggests urothelial origin. The coexpression of two of three non-UROIII markers (THR, HMWCK, CK20) suggests urothelial origin but requires clinicopathologic correlation. The results of the study indicate a role for an antibody panel that includes UROIII, THR, HMWCK, and CK20 in the diagnosis of urothelial tumors.     

Short telomeres and chromosome instability prior to histologic malignant progression and cytogenetic aneuploidy in papillary urothelial neoplasms

PurposeEvaluation of the relationships existing among 3 histologic types of urothelial tumors, chromosomal instability, and telomere length.Patients and methodsWe examined 37 consecutive cases of papillary urothelial neoplasm, from which 26 (70.3%) were suitable for karyotype analysis, comprising 7 papillary urothelial neoplasms of low malignant potential (PUNLMPs), 10 low-grade papillary urothelial carcinomas (PUCs), and 9 high-grade PUCs. We performed karyotype and anaphase bridge analyses, and measured telomere lengths by quantitative fluorescence in situ hybridization.ResultsPUNLMPs were always diploid and had anaphase bridges. Low-grade PUCs showed diploidy (n = 2), hypoploidy (n = 4) and polyploidy (n = 4), and high-grade PUCs showed diploidy (n = 1) and polyploidy (n = 8); both had anaphase bridges. The incidence of anaphase bridges did not differ significantly between PUNLMPs and high-grade PUCs (P = 0.105). The telomere lengths of PUNLMP, low-grade PUC, and high-grade PUC, expressed as mean telomere fluorescence units (TFU)±SD, were 7906±3197, 4893±1567, and 3299±1406, respectively. The differences among the 3 groups were significant. However, 42.9% of the PUNLMPs had shorter telomeres than the mean value for low-grade PUCs, and 30.0% of the low-grade PUCs had shorter telomeres than those for high-grade PUCs. There was an inverse correlation between telomere length and the incidence of anaphase bridges.ConclusionsPUNLMP appears to progress to low-grade PUC and high-grade PUC in association with telomere shortening and chromosomal instability. Our data suggest that critically shortened telomeres cause chromosomal instability during progression of papillary urothelial neoplasms.     

Bladder cancer in Sri Lanka: Experience from a tertiary referral center

BACKGROUND: Bladder cancer is one of the most common malignancies occurring worldwide. No published data exists on bladder cancer in Sri Lanka. The objective of the study was to determine the clinicopathological characteristics of histologically confirmed transitional cell carcinoma (TCC) of the bladder in Sri Lanka. METHODS: Three hundred and one patients were diagnosed with primary bladder cancer during a 7.5-year period from 1993 to 2000. Two hundred and eighty-one patients (239 men and 42 women; mean age, 66 years; range, 26-88) with TCC of the bladder were evaluated with regard to clinical presentation, cystoscopic findings and histopathological data. RESULTS: Transitional cell carcinoma accounted for 93.4% of primary bladder cancer. There was a male predominance with a sex ratio of 6:1. The majority of patients (63.7%) were in the 7th and 8th decades of life. Painless hematuria was the most common presenting symptom (52.7%), followed by painful hematuria (39.2%). The median duration of hematuria for all TCC patients, as well as for muscle-invasive TCC patients, was 3 months. Papillary configuration at cystoscopy, was found in 89.7% of non-invasive urothelial tumors. In contrast, 77.8% of invasive TCC patients had a solid/mixed tumor configuration. One hundred and forty-five patients (51.6% of TCC) had non-invasive urothelial tumor and 136 patients (48.4%) had muscle-invasive disease. In the non-invasive urothelial tumor category, 61 patients (42.0%) had pTa tumors and 84 patients (58.0%) had pT1 tumors. Of newly diagnosed TCC cases, 5.3% were found to be T1G3 urothelial carcinomas. Fifty-six patients (38.6%) with non-invasive urothelial tumor had a tumor greater than 5 cm in size. CONCLUSIONS: More than 90% of primary bladder tumors in Sri Lanka are TCC, with nearly half the patients having muscle-invasive diseases on initial presentation. Even in non-invasive urothelial tumors, the majority (58.0%) have lamina propria invasion.     

Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: a mutational analysis with immunohistochemical correlation

The infrequent association of serous borderline tumors (SBTs) with invasive serous carcinoma has led to the view that SBTs are unrelated to invasive serous carcinoma. Nonetheless, mortality associated with SBTs is generally attributed to malignant transformation, and traditionally these tumors have been designated as "carcinomas of low malignant potential." Previous immunohistochemical studies evaluating p53 expression and molecular genetic studies evaluating mutational status have reported that p53 overexpression and mutations are infrequent in SBTs and occur in as many as 50% to 80% of invasive serous carcinomas. The different methodologies for determining p53 status and the failure to correlate the findings with tumor grade make these studies difficult to interpret. The current study was undertaken to overcome these deficiencies and to reconcile the relationship of SBTs to invasive serous carcinoma by performing a morphologic, immunohistochemical, and molecular genetic analysis comparing SBTs with low- and high-grade serous carcinoma. The molecular genetic analysis used a highly stringent, carefully designed nucleotide-sequencing method. A total of 96 sporadic serous tumors including 25 SBTs (11 atypical proliferative serous tumors and 14 intraepithelial low-grade serous carcinomas [noninvasive micropapillary serous carcinomas, MPSCs]), 12 low-grade serous carcinomas (invasive MPSCs), and 59 high-grade serous carcinomas were analyzed for their p53 mutational status of exons 5 to 9. Functional mutations, defined as mutations resulting in the alteration of the structure of the encoded protein, were detected in 30 of 59 (50.8%) high-grade serous carcinomas and 1 (8.3%) of 12 low-grade invasive serous carcinomas compared with 2 (8%) of 25 SBTs, both of these in intraepithelial low-grade serous carcinomas (noninvasive MPSCs). The similar frequency of p53 mutations in SBTs and low-grade invasive serous carcinomas in contrast to the significantly higher frequency of p53 mutations in high-grade serous carcinomas (P < 0.0005) suggests a common lineage for SBTs and low-grade invasive serous carcinomas and supports the view that SBTs are unrelated to the usual type of invasive serous carcinoma, which is a high-grade neoplasm. Mutational status was also correlated with p53 immunoreactivity. Although p53 immunoreactivity is generally higher in those specimens containing mutant p53, immunostaining is neither sufficiently specific nor sensitive enough to predict p53 mutations. The molecular genetic findings confirm our hypothesis of dual pathways of serous carcinogenesis based on previous analyses of KRAS and BRAF mutations on the same set of cases in which KRAS and BRAF mutations were found in 60% of SBTs and low-grade serous carcinoma but not in high-grade serous carcinomas. Based on these studies, we have proposed a model of serous carcinogenesis in which SBTs are the precursors of low-grade serous carcinomas whereas the usual type of invasive serous carcinoma is a high-grade neoplasm that develops "de novo" from in situ alterations in epithelial inclusion cysts.