具有内翻生长特征的尿路上皮增生性病变的临床病理学研究

目的 研究伴内翻生长特征的尿路上皮增生性病变的临床病理特征,探讨免疫组织化学和多点荧光原位杂交在其鉴别诊断中的作用.方法 收集具有内翻生长特征的尿路上皮病变41例,分为内翻乳头状瘤、内翻生长型尿路上皮癌、旺炽型von Brunn细胞巢,用多点荧光原位杂交方法检测其3、7、17号染色体获得和9p21缺失;免疫组织化学EnVision法标记p53、CK20和Ki-67;并对12例进行随访.结果 (1)内翻乳头状瘤12例,平均1.2 cm,由互相连接的细胞索或巢在固有膜内生长,细胞索相对较细而宽窄一致,细胞巢外呈栅栏状、内为流水状排列,可见鳞状分化,无细胞学上的异型性,无或偶见核分裂象,4例可见少量表面外生乳头,被覆少于6层的正常尿路上皮.(2)内翻生长型尿路上皮癌24例,平均2.1 cm,结构似内翻乳头状瘤,但细胞索较粗并宽窄不一,细胞巢粗大并不规则状,可形成实体结构,瘤细胞轻至中度异形,核分裂象1～8个/10 HPF,3例表面均未见外生性乳头,但表层尿路上皮有明显异型增生,有少量外生乳头者外生成分形态符合低级别或低度恶性潜能.(3)旺炽型yon Brunn细胞巢5例,平均0.9 cm,表面被覆正常或增厚的黏膜组织,固有膜内见巢状分布、大小不等、排列紧密的尿路上皮团伴有囊腔形成,细胞均无异型性,无或偶见核分裂象.多点荧光原位杂交:79.1%(19/24)的内翻生长型尿路上皮癌存在染色体异常阳性,而内翻乳头状瘤和旺炽型von Brunn细胞巢无阳性染色体异常.免疫组织化学:CK20仅在2例内翻生长型尿路上皮癌中弱表达,内翻乳头状瘤和旺炽型von Brunn细胞巢均为阴性;16例内翻生长型尿路上皮癌和1例内翻乳头状瘤中有5%～50%的瘤细胞弱表达p53;内翻生长型尿路上皮癌中1%～5%表达Ki-67,内翻乳头状瘤和旺炽型von Brunn细胞巢均低于1%.随访:2例内翻生长型尿路上皮癌经多次复发后为浸润性癌,行全膀胱切除后仍发生远处转移.内翻乳头状瘤无复发.结论 伴内翻生长特征的尿路上皮增生性病变在良恶性病变中存在形态学上的重叠,但内翻生长型尿路上皮癌在形态及免疫组织化学上有独特特征.多点荧光原位杂交在鉴别诊断中有辅助作用.

Abstract：

Objective To study the clinieopathologie features of urothelial hyperplastie lesion with an endophytic growth pattern and the role of immunohistochemistry and muhitargeted fluorescence in situ hybridization(FISH)in the differential diagnosis.Methods Forty-one cases of urothelial lesions exhibiting endophytic growth patterns were reviewed and reclassified as inverted papilloma.urothelial carcinoma with an endophytic growth pattern,and florid von Brunn nest.The gains of chromosomes 3,7,and 17 and loss of 9p21 was detected by FISH,and performed immunohistochemical staining for CK20,p53,and Ki-67.Follow-up data of 12 cases were obtained.Results (1)Twelve inverted papillomas sized 1.2 cm in average.consisted of anastomosing cords and nests with uniform width distribution involving the lamina propfia,the central portion contained streaming cells with squamous metaplasia,and the periphery showed palisading.No or rare atypia and mitosis were found.Focal exophytic papillary component lined by less than 6 layers of normal urothelium were observed in 4 cases.(2)Twenty-four urothelial carcinomas with an endophytic growth pattern sized 2.1 cm in average,demonstrated the similar architecture with inverted papilloma,but exhibited thick columns and variable thickness ofthe cords,irregular size and shape of large nests with transition into solids.Mild to moderate cytologic atypia was shown,and mitotic figures ranged 1 to 8 per 10 HPFs.Exophytic papillary component was not observed in 3 cases.but the superficial urothelium showed dysplasia,while coexisted exophytie component in other eases was associated with low malignant potential or low grade tumor.(3)Five florid von Brunn nests sized 0.9 cm in average,had normal or hyperplastic urothelium,variable nests with cysts compacted in lamina propria,no cytologic atypia and mitosis.Twenty-one of 24(79.1%)urothelial carcinomas with an endophytie growth pattern displayed abnormally positive results by muhitargeted FISH,whereas all inverted papillomas and florid yon Brunn nests were negative.Immunohistochemically,CK20 Was weakly positive in 2 cases of urothelial carcinoma with an endophytic growth pattern,and negative in all inverted papillomas and florid yon Brunn nests.p53 weakly stained 5%to 50%nuclei of the tumor cells in 16 cafles of urothelial carcinomas with an endophytie growth pattem and 1 inverted papiHoma.1%-5%tumor ceUs expressed Ki-67 in urothelial carcinoma with an endophytic growth pattern,and less than 1%in inverted papiHoma and florid von Brunn nests.Follow-up study revealed that 2 cases of urothelial carcinoma with an endophytic growth pattern had developed invasive carcinoma,underwent cystectomy,and metastasized remotely.No recurrence occurred in cases of inverted papilloma.Conclusions Benign and malignant urothelial lesions with an endophytic growth pattern present histologie overlapping.Urothelial carcinoma with an endophytie growth pattern displays unique characteristics in morphology and immunohistochemistry.Multitargeted FISH analysis is helpful in the differential diagnosis.     

具有内翻生长特征的尿路上皮增生性病变的临床病理学研究

目的 研究伴内翻生长特征的尿路上皮增生性病变的临床病理特征,探讨免疫组织化学和多点荧光原位杂交在其鉴别诊断中的作用.方法 收集具有内翻生长特征的尿路上皮病变41例,分为内翻乳头状瘤、内翻生长型尿路上皮癌、旺炽型von Brunn细胞巢,用多点荧光原位杂交方法检测其3、7、17号染色体获得和9p21缺失;免疫组织化学EnVision法标记p53、CK20和Ki-67;并对12例进行随访.结果 (1)内翻乳头状瘤12例,平均1.2 cm,由互相连接的细胞索或巢在固有膜内生长,细胞索相对较细而宽窄一致,细胞巢外呈栅栏状、内为流水状排列,可见鳞状分化,无细胞学上的异型性,无或偶见核分裂象,4例可见少量表面外生乳头,被覆少于6层的正常尿路上皮.(2)内翻生长型尿路上皮癌24例,平均2.1 cm,结构似内翻乳头状瘤,但细胞索较粗并宽窄不一,细胞巢粗大并不规则状,可形成实体结构,瘤细胞轻至中度异形,核分裂象1～8个/10 HPF,3例表面均未见外生性乳头,但表层尿路上皮有明显异型增生,有少量外生乳头者外生成分形态符合低级别或低度恶性潜能.(3)旺炽型yon Brunn细胞巢5例,平均0.9 cm,表面被覆正常或增厚的黏膜组织,固有膜内见巢状分布、大小不等、排列紧密的尿路上皮团伴有囊腔形成,细胞均无异型性,无或偶见核分裂象.多点荧光原位杂交:79.1%(19/24)的内翻生长型尿路上皮癌存在染色体异常阳性,而内翻乳头状瘤和旺炽型von Brunn细胞巢无阳性染色体异常.免疫组织化学:CK20仅在2例内翻生长型尿路上皮癌中弱表达,内翻乳头状瘤和旺炽型von Brunn细胞巢均为阴性;16例内翻生长型尿路上皮癌和1例内翻乳头状瘤中有5%～50%的瘤细胞弱表达p53;内翻生长型尿路上皮癌中1%～5%表达Ki-67,内翻乳头状瘤和旺炽型von Brunn细胞巢均低于1%.随访:2例内翻生长型尿路上皮癌经多次复发后为浸润性癌,行全膀胱切除后仍发生远处转移.内翻乳头状瘤无复发.结论 伴内翻生长特征的尿路上皮增生性病变在良恶性病变中存在形态学上的重叠,但内翻生长型尿路上皮癌在形态及免疫组织化学上有独特特征.多点荧光原位杂交在鉴别诊断中有辅助作用.     

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.     

Inverted urothelial papillomas with foamy or vacuolated cytoplasm

Inverted papillomas of the bladder are uncommon benign neoplasms characterized by endophytic growth of urothelial cells as anastomosing cords, displaying minimal cytologic atypia. Reports of inverted papilloma associated with urothelial carcinoma or urothelial carcinoma arising within inverted papilloma highlight the difficulties in evaluating urothelial lesions with inverted growth patterns. Within the spectrum of findings in inverted papilloma, vacuolization and foamy (xanthomatous-appearing) cytoplasmic changes have not been previously reported. In the current study, we present 5 novel cases of inverted papilloma involving 2 men and 3 women ranging in age from 48 to 88 years, who presented with microhematuria (n = 3) or irritative symptoms (n = 2). Cystoscopically, the lesions were polypoid (n = 3), pedunculated (n = 1), or solid (n = 1), measured between 0.7 and 2.5 cm, and were all located at the trigone or bladder neck. Morphologically, all cases had some component of usual inverted papilloma along with areas displaying foamy or vacuolated cytoplasm encompassing 30% to 90% of the lesion. These "clear cells" were seen both in distinct regions within the biopsy and, more frequently, intermingled with usual inverted papilloma cells. In 3 of 5 cases, these findings were sufficiently unusual to cause confusion with urothelial carcinoma. The diagnostic dilemma encountered in these cases of inverted papilloma with foamy or vacuolated cytoplasm warrants their distinction from other benign and malignant urothelial lesions with inverted growth and/or clear cell features.     

Urothelial carcinoma of the upper urinary tract: inverted growth pattern is predictive of microsatellite instability

Urothelial carcinoma of the renal pelvis and ureter may develop as a manifestation of hereditary nonpolyposis colorectal cancer syndrome (HNPCC), a disorder characterized by mutation or inactivation of a number of DNA mismatch repair genes and detectable as microsatellite instability (MSI). Some urothelial carcinomas display areas of endophytic, or inverted, growth. In this study, urothelial cancers of the upper urinary tract (n = 132) from patients treated at 2 tertiary care centers were studied to identify an association between growth pattern and MSI. Thirty-five neoplasms were microsatellite unstable (26.5%), and MSI was more frequent in papillary lesions than in sessile urothelial cancers (P = .033). The amount of inverted growth was estimated as a percentage of the total tumor. The interobserver and intraobserver concordance in recognizing inverted growth was good, and 65.7% of microsatellite-unstable tumors exhibited at least 20% of an inverted growth component, compared with only 17.5% of microsatellite-stable tumors (P < .0001). In this series, inverted growth predicted MSI with a sensitivity and specificity of .82. Inverted growth in urothelial carcinomas of the upper urinary tract may serve as a marker lesion for MSI and may help identify patients who should be offered testing for HNPCC.     

Urothelial eddies in papillary urothelial neoplasms: a distinct morphologic pattern with low risk for progression

We encountered an undescribed histologic feature of papillary urothelial neoplasms: “urothelial eddy”, which was histologically reminiscent of squamous eddy of irritated follicular keratosis of the skin. A review of 756 patients with transurethral resection of bladder tumor revealed 10 patients (1.3%) of papillary urothelial neoplasms with urothelial eddies. All cases were male with a median age of 65 years. Urothelial eddies were characterized by small ovoid nests of ovoid to spindle cells arranged in an onion-skin pattern with fine cytoplasmic processes within wide intercellular space. The cytoplasmic processes mimicked intercellular bridges but ultrastructurally were cytoplasmic microvillous projections. They were of papillary urothelial neoplasm of low malignant potential in seven patients and low-grade urothelial carcinoma in three patients. Nine patients presented as non-invasive tumor and one patient showed microinvasion within papillary stalks. Six patients showed an inverted growth pattern. Their immunoprofile was more similar to that of conventional urothelial carcinoma rather than squamous cell carcinoma: high expressions of GATA3, S100P, uroplakin III, and cytokeratin 7; and low expressions of high molecular weight cytokeratin and p53. The Ki-67 labeling index was low (mean and median values, 2% each). During the follow-up period (mean, 88.7 months), four patients, including the microinvasive patient, showed recurrence with the same grade and stage but neither progressed into muscle-invasive tumor nor caused death. Our results suggest that urothelial eddy is a rare aberrant histology of papillary urothelial neoplasms with indolent behavior and should be discriminated from squamous differentiation of urothelial carcinoma, which has a poor prognosis.     

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.     

Benign and low-grade papillary lesions of the urinary bladder: a review of the papilloma-papillary carcinoma controversy, and a report of five typical papillomas

The controversial topic concerning the most appropriate nomenclature for low-grade papillary lesions of the urinary bladder is reviewed on the basis of the literature and the authors' experiences. This undertaking was prompted by a recent report in which use of the designation "papilloma" was advocated for lesions that generally had been diagnosed as grade 1 papillary urothelial carcinoma. The literature indicates that 10% to 20% of patients with a noninvasive low-grade papillary tumor of the bladder will later have invasive bladder cancer. This significant outcome in a minority of such patients warrants very careful follow-up for the group as a whole, irrespective of the terminology used. The authors contrast the features of papillary urothelial carcinoma with a series of five cases, which they interpret as true papillomas. They believe that these low-grade papillary lesions can be distinguished from true papillomas and do not favor a change in terminology. Some of the problems in the evaluation of inverted papilloma and inverting urothelial carcinoma are briefly reviewed as are other selected papillary lesions of the urinary bladder.     

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.     

The macrofollicular variant of papillary thyroid carcinoma: a study of 17 cases.

We report 17 cases of a distinctive variant of encapsulated papillary carcinoma that is likely to be confused with macrofollicular adenoma or nodular goiter. The tumors showed the unusual combination of macrofollicles and foci of the conventional follicular variant of papillary carcinoma. Macrofollicles occupied over 50% of the cross-sectional areas of the tumors. The macrofollicles were lined either by cells with large ground-glass nuclei, cells with large but less pale nuclei with stippled chromatin, or cuboidal cells with hyperchromatic nuclei. Solid foci were present in four tumors, and a focal insular growth pattern was noted in a fifth tumor. All patients were females ranging in age from 15 to 69 years (mean, 35.4 years). Despite the large size of the tumors (mean diameter, 4.8 cm), only two metastasized to cervical lymph nodes. One of these neoplasms showed extrathyroidal extension, while the other widely invaded the thyroid tissue through the tumor capsule. Multicentric foci of papillary carcinoma with a follicular nonsclerosing growth pattern were demonstrated in the contralateral lobe in two thyroid glands. All patients with follow-up were alive and symptom-free 2 months to 6 years following surgery.     

Micropapillary urothelial carcinoma of the upper urinary tract: Clinicopathologic study of five cases

We report 5 cases of micropapillary urothelial carcinoma (MPUC) involving the renal pelvis (2), renal pelvis and ureter (2), and proximal ureter (1). The patients were 2 women and 3 men, ages 65 to 92 years (mean, 76.0 years). All tumors showed a high-grade transitional cell carcinoma component, and in 3 cases, there also were areas of in situ carcinoma. The case involving only the ureter occurred in a 65-year-old man with a history of nephrectomy 12 years previously for urothelial carcinoma of the renal pelvis. The tumor recurred in the ureteral stump. In all cases, areas displaying micropapillary architecture were observed. In 2 cases the micropapillary areas were noninvasive; in 1 case a pure invasive pattern was seen; and in 2 cases a mixed invasive and noninvasive pattern was present. the micropapillary pattern was invasive; and the case involving the ureteral stump contained invasive and noninvasive micropapillary carcinoma. All patients died of their tumors from 3 to 24 months after initial diagnosis. MPUC involving the renal pelvis and ureter is associated closely with advanced stages of disease and has highly aggressive behavior. Recognition of this growth pattern is important for prognosis and avoiding misdiagnosis with papillary renal cell carcinoma and other tumors.     

Atypia in inverted urothelial papillomas: pathology and prognostic significance

Inverted papillomas of the bladder are considered benign urothelial neoplasms, based on their histology and clinical course. There are scant data on inverted papillomas with atypical features. Whether to designate them as inverted papillomas with atypia or low-grade transitional cell carcinomas with inverted features is controversial. In the present study, 11 cases of inverted papillomas with atypia and 10 controls of classic inverted papillomas without atypia were collected from 2 institutions. The inverted papillomas with atypia had the typical architectural features of inverted papillomas consisting of thin anastomosing trabeculae of urothelium growing downward into the stroma without an exophytic papillary component. The atypical areas in the current series were focal, with other areas exhibiting the benign cytology of classic inverted papillomas. Cases with atypia were subdivided into the following groups: (1) 5 cases notable for areas containing prominent nucleoli, (2) 2 cases with foci with atypical squamous features, (3) 2 cases with areas of dysplasia, approaching the level of carcinoma in situ, (4) 1 case with degenerative-appearing multinucleated giant cells, and (5) 1 case notable for nests of atypical squamous cells associated with large, atypical squamoid cells with a pagetoid appearance in addition to degenerative-appearing multinucleated giant cells. Ki67 was slightly increased in 1 case, with focal dysplasia approaching carcinoma in situ and in 1 case with prominent nucleoli (increased Ki67 in both the atypical and non-atypical areas) and in the case with atypical squamous, pagetoid, and giant cells (no increased Ki67 in the atypical components). Two of the atypical inverted papilloma cases with prominent nucleoli demonstrated an increase in p53 staining throughout the lesions. Cytokeratin (CK) 20 staining was negative in all cases of inverted papillomas. No significant increase in Ki67 staining was found in any of the 10 control cases; increased p53 staining was seen in 1 control case. CK20 staining was negative in the 10 control cases. In the 11 cases with atypia, clinical follow-up revealed no history of prior or subsequent bladder neoplasms. In the cases reviewed, most inverted papillomas with atypia did not demonstrate significantly increased cellular proliferation in comparison with inverted papillomas without atypical features. To date, there has been no association with urothelial carcinoma in the individuals diagnosed with atypical inverted papillomas. These findings suggest that these lesions are currently best classified as inverted papillomas with atypia, not as low-grade transitional carcinomas, and that they merit continued evaluation as a distinct group.     

Inverted variant of urothelial carcinoma of the urinary bladder: a report of three cases and a proposal for a new clinicopathologic entity

Inverted urothelial carcinoma (UC) without papillary areas is very rare; only 31 cases of three papers have been reported. The author herein reports three additional cases, and proposes the term “inverted variant” (IV) of UC. The materials were 3 cases of IV of UC, 5 cases of inverted papilloma (IP), and two cases of nested variant (NV) of UC. The three cases of IV of UC consisted of 56-year-old woman, 63-year-old man, and 78-year-old man. Presenting symptoms were hematuria in all cases. The cystoscopic findings were elevated tumors without papillary proliferations in all cases. The treatment was transurethral tumor resection (TUR-BT) in all cases. The sizes was 0.6 cm, 0.5 cm, and 3 cm. Microscopically, IV of UC showed inverted growth of atypical cells without papillary proliferations. Compared to IP, the inverted growth pattern was similar, but cytological atypia and thick trabeculae were noted in IV of UP while they were absent in IP. Compared to NV of UC, the growth pattern is different; NV of UC showed nested and vague tubular pattern. The cellular atypia is more pronounced in IV of UC than NV of UC. Immunohistochemically, p53 expression was seen in all the cases of IV of UC and in all the cases of NV of UC, while p53 expression was negative in all the cases of IP. Ki-67 labeling index was 25, 30 and 40% in IV of UC, 15 and 30% in NV of UC, and 3, 5, 6, 7, 9% in IP. Invasive features were seen in 1 case of IV of UC and 2 cases of NV of UC. In all cases of IV of UC, IP, and NV of UC, the TUR-BT, but one case of IV of UC, showed no recurrence after TUR-BT, while one case of IV of UC showed a recurrence. In conclusion, the IV and UC were structurally and cytologically very different from the NV of UC. The IV of UC was structurally similar to IP, but cellular atypia and thickened trabeculae were seen in IV and UC. p53 expression and Ki-67 labeling status were entirely different between in IV of UC and IP. The author proposes the term of IV of UC as a new clinicopathological entity.     

Collecting duct carcinoma: an entity to be redefined?

Collecting duct carcinomas (CDCs) are highly aggressive tumors with poor survival at 1 year and are often metastatic at the time of diagnosis. It has been shown that patients may have better survival when treated with a chemotherapy regimen used for urothelial carcinoma. Such tumors must therefore be recognized, but their pathological diagnosis remains difficult. The two main differential diagnoses are renal pelvis urothelial carcinoma with infiltration of the kidney and/or high-grade and high-stage papillary renal cell carcinoma. The aim of our study was to compare the immunophenotype of 14 CDCs with 6 renal pelvis urothelial carcinomas (RPUC) infiltrating the medulla. The following markers were evaluated: ulex europeus aglutinin (UEA), peanuts aglutinin, vimentin and aquaporin 3 (AQP-3), a membrane component of normal collecting duct and urothelial cells. We were able to define a reproductive urothelial phenotype AQP-3+, vimentin– and UEA+. Among the 14 CDCs, 10 cases demonstrated this immunophenotype. It coincided with an urothelial-like trabecular and tubular pattern. In contrast, the 4 remaining papillary CDCs had the inverse pattern, AQP-3–, vimentin+ and UEA–. These results suggest that: (1) the trabecular and tubular variant of CDC with the urothelial AQP-3+, vimentin– phenotype can be included in the spectrum of urothelial diseases; (2) the papillary variant probably does not belong to the same entity; (3) AQP-3 is a marker of interest for improving the histological classification of CDC and unclassified aggressive renal tumors.     

Neoplasms of the upper urinary tract: a review with focus on urothelial carcinoma of the pelvicalyceal system and aspects related to its diagnosis and reporting

Tumors of the renal pelvis account for approximately 7% to 8% of all renal malignancies, greater than 90% of these are of urothelial (transitional cell) origin. These tumors more typically occur in the sixth to eight decade with a slight male preponderance. Varying risk factors for urothelial carcinomas of the upper tract are recognized including environmental and occupational hazards, chemotherapeutic exposure, and previous history of urinary bladder or ureteral carcinomas. Tumor multifocality is frequent and additional tumors may arise in the ureter, bladder, or on the contralateral side. The histopathologic nuances presented by urothelial carcinoma in this region are generally similar to those in the urinary bladder. Though the World Health Organization 2004/International Society of Urological Pathology system used in the bladder is customarily also employed for grading of urothelial tumors of this region, its prognostic significance at this site is not entirely clear as most tumors are treated with nephroureterectomy irrespective of the grade of the tumor. Histologic grade may be an independent prognostic factor in papillary pT1 tumors; however, most pT2 and higher stage tumors tend to be nonpapillary and of higher grade. Despite advances in treatment modalities with sophisticated endoscopic techniques, tumor stage remains the most important prognostic factor. There are several confounding issues related to staging such as the variable presence and thickness of subepithelial connective tissue and muscularis in the renal calyces, renal pelvis, and the ureter; intratubular pagetoid cancer spread (pTis vs. pT3); and assessing invasion in papillary neoplasms with endophytic or inverted growth. Careful gross examination with adequate sampling and understanding the microanatomy of the pelvicalyceal wall are crucial for accurate stage assignment. Poor fixation of large friable tumors and processing artifacts may compound difficulties in accurate staging. This review focuses on urothelial carcinoma of the upper tract highlighting issues related to its diagnosis, staging, and reporting.     

Prevalence of six types of human papillomavirus in inverted papilloma and papillary transitional cell carcinoma of the bladder: an evaluation by polymerase chain reaction.

AIMS: To study the prevalence of high risk oncogenic human papillomaviruses (HPV) in inverted papilloma and papillary transitional cell carcinoma of the bladder. METHODS: Ten cases of inverted papilloma and 20 cases of papillary transitional cell carcinoma of the bladder from Chinese patients in Hong Kong were examined for the presence of HPV type 6, 11, 16, 18, 31, and 33 genomes using the polymerase chain reaction and HPV type specific primer probe combinations on paraffin wax embedded biopsy specimens. RESULTS: Of the 10 cases of inverted papilloma, cases 1 and 6 showed the presence of HPV types 16 and 18, respectively. Six of the 20 papillary transitional cell carcinomas were positive for HPV type 18. The other HPV types were not detected. CONCLUSIONS: HPV type 18 was found in 60% and 30% of cases of inverted papilloma and papillary transitional cell carcinoma of the bladder, respectively. These tumours were rarely associated with HPV types 6, 11, 16, 31, and 33. The role of HPV type 18 in oncogenesis of inverted papilloma and transitional cell carcinoma of the bladder requires further studies.     

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.     

A cribriform urothelial neoplasm of the renal pelvis: an adenoid cysticlike variant of inverted urothelial papilloma or florid ureteritis cystica?

Tumors with cribriform appearance, similar to that of salivary gland adenoid cystic carcinoma, have been described at various anatomic sites. We present an unusual polypoid tumor, discovered incidentally, in the renal pelvis of an elderly man. The mass displayed a prominent cribriform architecture, akin to adenoid cystic carcinoma with an immunophenotype that supported a urothelial origin. Because of its lack of significant invasive growth and other adverse morphologic features, this lesion will likely behave in a banal fashion. This cribriform urothelial neoplasm of the renal pelvis may, in fact, represent a variant of an inverted urothelial neoplasm with a prominent cystic component or florid ureteritis cystica. It is important for pathologists to recognize this growth pattern as a possible variant of urothelial tumors.     

Schneiderian papillomas: a clinicopathologic study of 67 cases

The clinical and pathologic features of schneiderian papillomas were studied in 67 patients. There were 40 male and 27 female patients, and the mean age at diagnosis was 49 +/- 17.9 (SD) years. Nasal obstruction or perception of a nasal mass was the most common presenting symptom; mean duration of symptoms was 10.8 +/- 15.8 (SD) months. Almost equal numbers of papillomas had predominantly endophytic (inverted) (n = 32) and predominantly exophytic (fungiform) (n = 30) patterns, and five had mixed patterns. Multiple morphologic variables were evaluated in the initial specimens, including cytologic atypia and number of mitotic figures; there were no statistically significant correlations between these variables and biologic behavior. Of the 39 patients for whom follow-up information was available (mean follow-up period, 38.6 months), six patients (all with predominantly endophytic patterns) had copresented with schneiderian papillomas and carcinomas. The remaining 33 patients initially had only benign schneiderian papillomas. In these 33 patients, recurrences developed in 11 (33 per cent), local invasion in two (6 per cent) (both with inverted papillomas), and epidermoid carcinoma in one (3 per cent) (with an inverted papilloma). Three patients had evidence of disease when last examined, and two patients had died of disease (both after copresentation with schneiderian papillomas and carcinomas). The continued use of the term inverted papilloma (endophytic pattern) as a specific subset of schneiderian papillomas is recommended, as all serious complications, including progression to local invasion, copresentation with carcinoma, and development of carcinoma, were associated with these lesions.     

Nested variant of urothelial carcinoma

Nested variant of urothelial carcinoma is a rare neoplasm that is histologically characterized by large numbers of small, closely packed, haphazardly arranged, poorly defined, confluent irregular nests of bland-appearing urothelial cells infiltrating the lamina propria and the muscularis propria. Due to the cells' deceptively bland appearance, the tumors are sometimes misdiagnosed as benign lesions, leading in some cases to a significant delay in establishing the correct diagnosis and thus contributing to this neoplasm's advanced stage. Nested variant of urothelial carcinoma must be differentiated from the benign proliferative lesions of urothelium, such as von Brunn nests, cystitis cystica, cystitis glandularis, nephrogenic adenoma, inverted papilloma, and paraganglioma.