Low-grade Noninvasive Papillary Urothelial Carcinoma Research Articles

International Society of Urological Pathology (ISUP) Consensus Conference on Current Issues in Bladder Cancer. Working Group 2: Grading of Mixed Grade, Invasive Urothelial Carcinoma Including Histologic Subtypes and Divergent Differentiations, and Non-Urothelial Carcinomas.

The 2022 International Society of Urological Pathology (ISUP) Consensus Conference on Urinary Bladder Cancer Working Group 2 was tasked to provide evidence-based proposals on the applications of grading in noninvasive urothelial carcinoma with mixed grades, invasive urothelial carcinoma including subtypes (variants) and divergent differentiations, and in pure non-urothelial carcinomas. Studies suggested that predominantly low-grade noninvasive papillary urothelial carcinoma with focal high-grade component has intermediate outcome between low- and high-grade tumors. However, no consensus was reached on how to define a focal high-grade component. By 2004 WHO grading, the vast majority of lamina propria-invasive (T1) urothelial carcinomas are high-grade, and the rare invasive low-grade tumors show only limited superficial invasion. While by 1973 WHO grading, the vast majority of T1 urothelial carcinomas are G2 and G3 and show significant differences in outcome based on tumor grade. No consensus was reached if T1 tumors should be graded either by the 2004 WHO system or by the 1973 WHO system. Because of the concern for underdiagnosis and underreporting with potential undertreatment, participants unanimously recommended that the presence of urothelial carcinoma subtypes and divergent differentiations should be reported. There was consensus that the extent of these subtypes and divergent differentiations should also be documented in biopsy, transurethral resection, and cystectomy specimens. Any distinct subtype and divergent differentiation should be diagnosed without a threshold cutoff, and each type should be enumerated in tumors with combined morphologies. The participants agreed that all subtypes and divergent differentiations should be considered high-grade according to the 2004 WHO grading system. However, participants strongly acknowledged that subtypes and divergent differentiations should not be considered as a homogenous group in terms of behavior. Thus, future studies should focus on individual subtypes and divergent differentiations rather than lumping these different entities into a single clinicopathological group. Likewise, clinical recommendations should pay attention to the potential heterogeneity of subtypes and divergent differentiations in terms of behavior and response to therapy. There was consensus that invasive pure squamous cell carcinoma and pure adenocarcinoma of the bladder should be graded according to the degree of differentiation. In conclusion, this summary of the International Society of Urological Pathology Working Group 2 proceedings addresses some of the issues on grading beyond its traditional application, including for papillary urothelial carcinomas with mixed grades and with invasive components. Reporting of subtypes and divergent differentiation is also addressed in detail, acknowledging their role in risk stratification. This report could serve as a guide for best practices and may advise future research and proposals on the prognostication of these tumors.

Noninvasive papillary urothelial neoplasia (NIPUN): Renaming cancer

Papillary urothelial neoplasm of low malignant potential (PUNLMP) terminology remains controversial given its reported recurrence rate, its low interobserver diagnostic reproducibility, and its morphologic and molecular genetic overlap with low-grade noninvasive papillary urothelial carcinoma. By contrast, referring to any noninvasive tumor as a “carcinoma” is also controversial. PUNLMP and low-grade noninvasive papillary urothelial carcinomas cannot be reliably distinguished from one another even by experienced pathologists. As both tumors are treated in an identical manner and have similar rates of recurrence and progression, attempting to make this distinction is unnecessary and of little clinical value. These tumor types should therefore be combined into a single category for grading purposes. We propose that all tumors currently classified as either PUNLMP or low-grade noninvasive papillary urothelial carcinoma be termed low-grade noninvasive papillary urothelial neoplasms (NIPUN). This could improve interobserver reproducibility without sacrificing the prognostic utility of histologic grading. PUNLMP terminology should be discontinued and the term “carcinoma” should be reserved only for tumors showing histologic evidence of invasion.

Importance of cytokeratin-20 expression in papillary urothelial neoplasia

Purpose: The aim of this study is to determine the role of Cytokeratin 20 (CK20) expression in the diagnosis of papillary urothelial neoplasms of the bladder, and its relationship with histological grade, recurrence and other prognostic factors.
 Materials and Methods: Patients diagnosed with papillary urothelial neoplasm of bladder transurethral resection (TUR) specimens between January 2011 and December 2016 were retrospectively analyzed. Of the 136 selected patients, 32 (24%) were diagnosed with urothelial papilloma, 8 (6%) with papillary urothelial neoplasm of low malignant potential (PUNLMP), 36 (26%) with low grade non-invasive papillary urothelial carcinoma (LGNIPUC), 12 (9%) with high grade non-invasive papillary urothelial carcinoma (HGNIPUC) and 48 (35%) were diagnosed with high grade invasive papillary urothelial carcinoma (HGIPUC). There was no patient diagnosed with LGIPUC. The correlation between CK20 expression and histological grade, tumor recurrence, presence of progression and presence/absence of invasion was investigated.
 Results: There was a significant difference between PUNLMP and LGNIPUK in terms of CK20 expression in favor of LGNIPUK. Also there was a significant correlation between histological grade, presence of invasion, recurrence, progression and CK20 expression in patients diagnosed with Papillary Urothelial Neoplasm. 
 Conclusion: This study supports that CK20 is an important marker in the differentiation between PUNLMP and LGNIPUC, as well as in the determination of histological grade in urothelial carcinomas.

Reappraisal of the papillary urothelial neoplasm of low malignant potential (PUNLMP).

Although the papillary urothelial neoplasm of low malignant potential (PUNLMP) diagnostic category was retained in the updated 2016 World Health Organisation (WHO) classification of tumours of the urinary system, there still exists a great deal of controversy regarding the biological behaviour of these tumours. We review PUNLMP tumours and histological grading with an emphasis on the histomorphological, genetic and clinical similarities between PUNLMP and low-grade non-invasive papillary urothelial carcinoma. A literature search using PubMed was performed. All relevant literature concerning PUNLMP and the grading of urothelial tumours was reviewed. PUNLMPs cannot be reliably distinguished from low-grade non-invasive papillary urothelial carcinomas based on the histomorphological criteria outlined in the WHO 2004/2016 classification system. PUNLMPs and low-grade non-invasive papillary urothelial carcinomas are not only morphologically similar, but also share similar molecular genetic alterations and a similar risk of recurrence and progression. In addition, there are no consensus recommendations for a different method of treatment and follow-up for these two tumour types. Attempting to distinguish PUNLMP from low-grade papillary urothelial carcinoma adds an unnecessary level of complexity to the grading and classification of urothelial tumours. We feel that PUNLMP terminology should be abandoned and that all such tumours should be classified as low-grade carcinomas until more objective determinants of clinical outcome can be established.

Amyloidosis of the bladder and association with urothelial carcinoma: report of 29 cases

The association of amyloidosis with certain neoplastic processes is well known. Amyloid uncommonly occurs in relationship with other epithelial neoplasms including urothelial carcinoma. Herein, we report 29 cases of amyloidosis in the bladder, 14 of which were found in relationship to urothelial carcinoma. With institutional review board approval. We searched pathology archives for cases of amyloidosis in the bladder. Clinical, laboratory, and surgical pathology records were reviewed, and data were recorded for all cases. Diagnosis of amyloid was made by Congo red stain showing apple-green birefringence on polarization microscopy and special studies in some cases. Twenty-nine cases of amyloid were identified in bladder specimens. Presentation as a mass lesion was the most common (n = 18). Immunohistochemical subtyping done in 17 cases showed transthyretin-type (n = 10), AL (n = 3), AA (n = 1), amyloid P (n = 1), and undetermined (n = 2) types of amyloid. Eighteen (62%) cases were classified as localized primary amyloidosis and 11 (38%) as secondary manifestation of systemic amyloidosis. In 14 (48%) cases, there was an associated urothelial carcinoma: 5 urothelial carcinoma in situ, 4 low-grade noninvasive papillary urothelial carcinoma, 2 high-grade noninvasive papillary urothelial carcinoma, and 3 high-grade invasive urothelial carcinoma. Associated urothelial carcinoma was present in 4 of 7 patients with systemic amyloidosis and 10 of 18 patients with localized amyloidosis, with the difference not being statistically significant (P = .45). Amyloidosis of the bladder is rare and presents as a mucosal mass or hematuria that may mimic urothelial carcinoma. In this study, we found urothelial carcinoma occurring in 48% of the cases in association with amyloidosis, a finding not previously reported. The relationship of amyloid in the bladder and urothelial carcinoma, although likely not causal, appears to be a unique finding not frequently seen with other solid tumors.

Nuclear features of infiltrating urothelial carcinoma are distinguished from low-grade noninvasive papillary urothelial carcinoma by image analysis.

Recent advances in computer technology have been made and image analysis (IA) has been introduced into pathological fields. The present study aimed to investigate the utility of IA for the evaluation of nuclear features and staining of immunohistochemistry (IHC) for Ki-67, p53 and GATA-binding protein 3 (GATA-3) in urothelial carcinoma tissue samples. A total of 49 cases of urothelial carcinoma tissue samples were obtained by transurethral resection of bladder tumors, which included 11 low-grade papillary urothelial carcinomas (LGPUCs), 1 non-invasive high-grade urothelial carcinoma and 37 infiltrating urothelial carcinomas (IUCs). Whole slide imaging (WSI) and IA were performed in Feulgen reaction and IHC-stained tissue samples. There was a significant difference in the average nuclear density, standard deviation (SD) of nuclear size and SD of nuclear minimum and maximum diameter between LGPUC and IUC, which is equivalent to the diagnostic features of IUC in nuclear variability, and hyperchromatic nuclei. In addition, the present study revealed that the SD of nuclear density was significantly different between the two groups. Regarding IA in IHC-stained tissue samples, Ki-67 was significantly overexpressed in IUC. Furthermore, the GATA-3 expression level in IUC samples with muscle invasion was significantly downregulated compared with that in non-muscle invasive tumors. The results of the present study suggest that IA in combination with WSI may be a beneficial tool for evaluating morphometric characteristics and performing semi-quantitative analysis of IHC.

Significance of a minor high-grade component in a low-grade noninvasive papillary urothelial carcinoma of bladder

To assess the clinicopathological features and prognostic significance of the presence of 5% or less high-grade component in otherwise low-grade noninvasive bladder urothelial carcinoma, referred to as mixed-grade (MG) urothelial carcinoma, we reviewed all archival cases with such diagnosis between 2005 and 2014. Clinicopathological and outcome parameters were compared to those in our previously reported low- and high-grade noninvasive bladder urothelial carcinoma cohorts (LGUC and HGUC, respectively). The study included 31 MG urothelial carcinomas. Mean patient age was 67.6 years, and mean follow-up was 39.7 months. Intravesical treatment was administered in 15 patients (48.4%). Recurrence occurred in 14 cases (45.2%): 10 as LGUC and 4 as HGUC; there was no stage progression. Mean time to progression was 9 months (5-17 months), and there was no death of disease. MG urothelial carcinoma stage progression and dead of disease rates were comparable to that of LGUC. MG urothelial carcinoma stage progression was significantly lower than that of HGUC, P = .002, using Pearson χ(2) test. MG urothelial carcinoma patients with no intravesical treatment had higher incidence rate of grade progression (25%) compared to LGUC patients (7.9%); however, the difference was not statistically significant. MG urothelial carcinoma had a prognosis closer to "pure" LGUC than "pure" HGUC. Untreated MG urothelial carcinoma may have a higher rate of grade progression than LGUC, although more data are needed before this issue can be definitively addressed. Until such data are available, it is reasonable to keep MG urothelial carcinoma as a distinct grade category with potential management implications.

Utility of ProEx C in the histologic evaluation of the neoplastic and nonneoplastic urothelial lesions

ProEx C is an antibody cocktail targeting the expression of topoisomerase IIα and minichromosome maintenance protein 2. ProEx C staining is being used mainly to assist in diagnoses of dysplasia in gynecological specimens. This study was designed to determine the utility of ProEx C in assessing the urothelial lesions. Sixty-four patient specimens were divided into 5 groups: group I, 22 benign; group II, 13 low-grade noninvasive papillary urothelial carcinoma; group III, 10 high-grade urothelial carcinoma in situ (flat lesion); and group IV, 19 high-grade noninvasive papillary and invasive urothelial carcinomas. ProEx C reactions were scored in basal, parabasal, intermediate, and superficial cell layers. A sample was recorded as positive when nuclear staining was seen in the cells of the intermediate and/or superficial layers. Of 22 cases in group I, 21 were negative for ProEx C with a specificity of 95%. Of 13 cases in group II, 11 had positive results with sensitivity of 85%. All cases in groups III and IV had positive staining pattern with ProEx C with a sensitivity of 100%. In this study, ProEx C stain had an overall 95% sensitivity and specificity with positive and negative predictive values of 98% and 91%, respectively, for detection of urothelial carcinoma. We conclude that ProEx C is effective in differentiating carcinoma in situ and benign urothelial lesions. It also resolves issues in low- versus high-grade papillary urothelial carcinomas. To our knowledge, this is the first publication on the diagnostic application of ProEx C in histopathology of the urothelial lesions.

Nephrogenic Adenoma

Nephrogenic adenoma of the urinary bladder, where they present most frequently, are typically confined to the lamina propria but can on occasion focally involve the superficial muscularis propria. Less commonly, nephrogenic adenoma involves the renal pelvis and ureter where again they almost always only involve the lamina propria. We identified 3 consult cases in which tubules of nephrogenic adenoma extensively involved the muscularis propria and focally infiltrated the perinephric adipose tissue, for which the contributing pathologists considered the diagnosis of adenocarcinoma. In 1 case, that of a 71-year-old man, the lesion was associated with a hemorrhagic renal cyst (3.0 cm) and a spontaneous retroperitoneal bleed (6.0 cm) of unknown origin. In the second case, that of a 73-year-old woman, 2 foci (2.2, 1.6 cm) were present in the renal pelvis. They developed after biopsy of a low-grade noninvasive papillary urothelial carcinoma in the same site complicated by perforation. The third case was that of a 20-year-old woman with ureteropelvic junction obstruction and severe hydronephrosis associated with renal calculi. In all cases, the lesions were positive for CK7 and PAX8. These 3 cases report the novel finding that nephrogenic adenoma can occasionally have a deep infiltrative pattern into perinephric adipose tissue, possibly as a result of either biopsy-associated perforation or extensive disruption due to hemorrhage or mechanical obstruction. Awareness of this worrisome infiltration pattern, although rare, can prevent a misdiagnosis of an infiltrating carcinoma.

Small Endoscopic Biopsies of the Ureter and Renal Pelvis

Technical advances in endoscopic equipment have led to increased ureteroscopic biopsies of the upper urinary tract, resulting in limited biopsy material. We retrospectively reviewed 76 consecutive mid-upper ureter and renal pelvis biopsies submitted for consultation from January 2004 to January 2009, where follow-up was obtainable. There were 49 (64.5%) males and 27 (35.5%) females. Thirty-nine (51.3%) of the biopsies were from the ureter with the remaining 37 (48.7%) from the renal pelvis. The mean age was 70 years for males and 71 for females (range: 24 to 89). At consultation, the most common diagnoses were benign urothelium (n=25, 32.9%); atypical (n=17, 22.4%); low-grade noninvasive papillary urothelial carcinoma (n=10, 13.2%); and high-grade noninvasive papillary urothelial carcinoma (n=8, 10.5%). In cases where a definitive diagnosis could not be reached on expert review, it was mainly because of the limited size of the biopsy, absence of papillary fronds, crush artifact, and distorted architecture. There were 7 major discrepancies between the outside and second opinion diagnosis, where all of the cases were initially diagnosed as an urothelial neoplasm, yet was non-neoplastic upon review. Strips of urothelium without well-developed fibrovascular cores, polypoid ureteritis/pyelitis, and reactive urothelium mimicked urothelial neoplasms. In 5 of these 7 cases, there was no gross lesion suspicious of a tumor present according to the urologist. Overall, 33 of the 44 (75%) cases with a mass noted by the urologist or by radiography was found to have a neoplasm at follow-up. Conversely, 24 of the 32 (75%) cases without a grossly suspected tumor had no neoplasm at follow-up. The association between the histologic presence of a neoplasm at follow-up and the presence of a clinically suspected tumor was highly significant (P<0.0001). Pathologists need to recognize that in almost 1 of the 4 renal pelvic/ureteral biopsies a definitive diagnosis cannot be made because of the inadequate tissue. Caution must be exercised in the evaluation of these limited specimens, especially in the absence of a clinically suspected tumor.