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Inverted papillary urothelial neoplasm of low malignant potential (Inverted PUNLMP). Inverted PUNLMP demonstrates inverted (endophytic) growth and resembles inverted papilloma, but in contrast, shows expanded and rounded cords and nests, composed of architecturally and cytologically bland urothelial cells (a and b). Inverted PUNLMP also lacks central streaming and peripheral palisading, as typically seen in inverted papilloma.
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Few larger studies have evaluated the long-term outcome after a diagnosis of papillary urothelial neoplasm of low malignant potential (PUNLMP), demonstrating broad range of recurrence and progression rates. Additionally, no study has addressed the outcome of PUNLMP exhibiting inverted growth. We evaluated the long term clinical outcome of primary p...
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Citations
... However, its preservation as a diagnostic entity is justified because of its intermediate recurrence and progression rates between papilloma and noninvasive low-grade papillary urothelial carcinoma. Recurrence rates of 18-20% and progression rates of 2-11% have been reported (Pan et al. 2010;Maxwell et al. 2015), with progression mainly to low-grade noninvasive papillary urothelial carcinoma and ~ 1% progression to invasive urothelial carcinoma (Maxwell et al. 2015). Limited data on the recurrence of inverted PUNLMP is available, but it seems rare (Maxwell et al. 2015). ...
... However, its preservation as a diagnostic entity is justified because of its intermediate recurrence and progression rates between papilloma and noninvasive low-grade papillary urothelial carcinoma. Recurrence rates of 18-20% and progression rates of 2-11% have been reported (Pan et al. 2010;Maxwell et al. 2015), with progression mainly to low-grade noninvasive papillary urothelial carcinoma and ~ 1% progression to invasive urothelial carcinoma (Maxwell et al. 2015). Limited data on the recurrence of inverted PUNLMP is available, but it seems rare (Maxwell et al. 2015). ...
... Recurrence rates of 18-20% and progression rates of 2-11% have been reported (Pan et al. 2010;Maxwell et al. 2015), with progression mainly to low-grade noninvasive papillary urothelial carcinoma and ~ 1% progression to invasive urothelial carcinoma (Maxwell et al. 2015). Limited data on the recurrence of inverted PUNLMP is available, but it seems rare (Maxwell et al. 2015). A population-based study describes 5-year recurrence rates of 21% and 42%, and tumor progression of 0.7% and 4% for PUNLMP and noninvasive low-grade papillary urothelial carcinoma respectively (Bobjer et al. 2022). ...
The Brazilian Society of Pathology Guidelines Project aims to provide recommendations for clinicians and pathologists based on the best available scientific evidence. It reviews the currently available and emerging histopathological and molecular aspects of bladder cancer that are necessary for the best patient’s management. This paper is a result of a combined effort of the Brazilian Society of Pathology, the Brazilian Society of Urology, and the Brazilian Society of Clinical Oncology to call attention to the essential pre-analytical issues, the required clinical information and specimen handling to allow proper diagnosis, grading, staging and characterization of the molecular aspects of bladder epithelial neoplasms.
... The PM group included dysplasia, hyperplasia and papillary urothelial neoplasm of low malignant potential (PUNLMP), and it is the most heterogeneous group in this work and we grouped all cases with any doubts due to their unequivocal nature, morphology, and treatment guidelines. 6,26,28,[29][30][31][32] FTIR imagining ...
Urothelial bladder carcinoma (BC) is primarily diagnosed with a subjective examination of biopsies by histopathologists, but accurate diagnosis remains time-consuming and of low diagnostic accuracy, especially for low grade non-invasive BC. We propose a novel approach for high-throughput BC evaluation by combining infrared (IR) microscopy of bladder sections with machine learning (partial least squares-discriminant analysis) to provide an automated prediction of the presence of cancer, invasiveness and grade. Cystoscopic biopsies from 50 patients with clinical suspicion of BC were histologically examined to assign grades and stages. Adjacent tissue cross-sections were IR imaged to provide hyperspectral datasets and cluster analysis segregated IR images to extract the average spectra of epithelial and subepithelial tissues. Discriminant models, which were validated using repeated random sampling double cross-validation, showed sensitivities (AUROC) ca. 85% (0.85) for the identification of cancer in epithelium and subepithelium. The diagnosis of non-invasive and invasive cases showed sensitivity values around 80% (0.84-0.85) and 76% (0.73-0.80), respectively, while the identification of low and high grade BC showed higher sensitivity values 87-88% (0.91-0.92). Finally, models for the discrimination between cancers with different invasiveness and grades showed more modest AUROC values (0.67-0.72). This proves the high potential of IR imaging in the development of ancillary platforms to screen bladder biopsies.
... Though PUNLMP poses a risk of recurrence and progression to low-grade urothelial carcinoma, it very rarely can advance to invasive carcinoma. [4,5] OM is a very rare phenomenon in bladder tumors, which can be occasionally seen in primary as well as metastatic invasive high-grade transitional cell carcinoma, and must be differentiated from sarcomatoid carcinoma. [6] Till date, no cases of PUNLMP with OM in young adults are described in the literature. ...
Urothelial tumors characteristically occur in elderly persons, more commonly in males with typical complaints of hematuria. Although few studies attempted to describe clinic-pathological features of urothelial malignancies in young patients, due to heterogeneity in the inclusion of age groups under "young patients" no reliable conclusions can be derived. Herein, we are describing an interesting case of papillary urothelial neoplasm of low malignant potential with osseous metaplasia in a 19-year-old chronic smoker young patient presented with chief complaints of abdominal pain with a review of the literature. KEY WORDS: Osseous metaplasia, papillary urothelial neoplasm of low malignant potential, urothelial tumor
... With 5 years clinical follow-up, progression to invasive disease was not seen in PUNLMP, while progression in low-grade and high-grade carcinoma was seen in 4% and 23%, respectively. Other more contemporary series have demonstrated the clinical utility of this classification 56,57 (Fig. 3). Over the years the ISUP/WHO classification has gained wide acceptance and have been endorsed by many societies, including the College of American Pathologists (CAP), the American Joint Commission of Cancer (AJCC), and the International Consortium on Cancer Reporting (ICCR), among others. ...
... In a study of 189 primary PUNLMPs, 12 had an exclusive inverted growth; no recurrence or progression was documented on follow-up for PUNLMPs that demonstrated exclusively inverted growth, compared with 21% recurrence for tumors with exophytic growth. 57 In a study of 81 patients with noninvasive low-grade papillary urothelial carcinoma, disease recurrence occurred in 41 patients (50.6%). Cases with an inverted pattern showed a lower recurrence rate in contrast to those with pure exophytic tumors (37.5% vs. 52.1%), ...
The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in bladder neoplasia with a focus on issues relevant to the practicing surgical pathologist for the understanding and effective reporting of bladder cancer, emphasizing particularly on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. The work is presented in 2 manuscripts. Here, in the first, we revisit the nomenclature and classification system used for grading flat and papillary urothelial lesions centering on clinical relevance, and on dilemmas related to application in routine reporting. As patients of noninvasive bladder cancer frequently undergo cystoscopy and biopsy in their typically prolonged clinical course and for surveillance of disease, we discuss morphologies presented in these scenarios which may not have readily applicable diagnostic terms in the WHO classification. The topic of inverted patterns in urothelial neoplasia, particularly when prominent or exclusive, and beyond inverted papilloma has not been addressed formally in the WHO classification. Herein we provide a through review and suggest guidelines for when and how to report such lesions. In promulgating these GUPS recommendations, we aim to provide clarity on the clinical application of these not so uncommon diagnostically challenging situations encountered in routine practice, while also importantly advocating consistent terminology which would inform future work.
... The next largest series had 189 Canadian patients with a median follow-up of 61 months. 24 Those authors reported rates of recurrence and progression similar to those in our series, with 20.1% of patients having any recurrence and 1% diagnosed with muscle-invasive disease over 5 years of follow-up. Another series reported on 53 patients from Japan who were diagnosed between 1976 and 1993. ...
Background
Nonmuscle‐invasive bladder cancer (NMIBC) has heterogeneous recurrence and progression outcomes. Available risk calculators estimate recurrence and progression but do not predict the recurrence stage or grade, which may influence downstream treatment. The objective of this study was to predict risk‐stratified NMIBC recurrence and progression based on recurrence tumor classification and grade.
Methods
In total, 2956 patients with NMIBC (<T2) who were diagnosed at Kaiser Permanente Northwest and Geisinger from 1994 to 2015 were identified. Recurrences were annotated for tumor classification and grade. Four risk‐stratified outcomes were created based on the tumor classification and grade of the recurrence: 1) any recurrence, 2) intermediate‐risk recurrence (Ta high grade, carcinoma in situ, T1 low grade) or higher, 3) high‐risk recurrence (T1 high grade) or progression (clinical T2), and 4) progression. Multivariable Cox proportional hazards regression was used to compute 1‐year and 5‐year risk estimates for each outcome based on initial tumor classification and grade.
Results
Over a median follow‐up of 29.4 months, there were 1062 recurrences (35.9%), including 111 progressions (3.8%). The adjusted hazard of high‐risk recurrence or progression increased, depending on initial tumor classification and grade: The adjusted hazard ratio was 2.60 (95% CI, 1.62‐4.15) for Ta high‐grade tumors, 4.74 (95% CI, 3.01‐7.47) for tumor in situ or Ta with carcinoma in situ, and 7.14 (95% CI, 4.97‐10.26) T1 high‐grade tumors. Using Ta high‐grade tumors as an example, the 1‐year and 5‐year predicted rates of adjusted risk of a high‐risk recurrence or progression were 4.4% and 7.9%, respectively.
Conclusions
The 1‐year and 5‐year predicted risk of high‐risk recurrences and progression increased with higher tumor classification and grade at diagnosis. These granular risk estimates may further inform risk‐stratified treatment and surveillance for patients with NMIBC.
... The close differential diagnosis of inverted PUNLMP is Inverted Papilloma. The growth pattern of inverted PUNLMP lacks central streaming and peripheral palisading which is a characteristic feature of inverted papilloma [6]. ...
... Out of 6.3% of inverted PUNLMP among 186 PUNLMP cases studied by Maxwell et al. all of these inverted PUNLMP revealed no recurrence of disease progression whereas overall rates of recurrence and progression to high grade carcinoma in case of PUNLMP with exophytic growth was 20.1 % and 1.6 % respectively with a mean follow up period of 61 months. Recurrence and progression was predominantly seen in male patients older than 50 years in their study [6]. However additional studies may be needed to verify present findings. ...
... IPUNLMP is also an uncommon urothelial neoplasm, but there are very limited data on the incidence and biologic behavior of this entity. In a study of 189 PUNLMPs, 12 cases exhibited pure inverted growth pattern, and no recurrence or progression was documented on follow-up [14]. Conversely, urothelial carcinomas with inverted or endophytic growth are malignant neoplasms with potential for recurrence, invasion, and metastasis [10]. ...
Background:
Most 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.
Methods:
Sixty 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.
Results:
A 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.
Conclusions:
The 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.
... Higher expression rate seen in PUNLMP compared to overt malignant cases in this study can be explained with the low number of the study population in this group. On the other hand, HE4 positivity might have predicted PUNLMP cases that would progress to a higher grade lesion, as the long-term outcome of these cases demonstrates a broad range of recurrence and progression rates [17]. ...
Background: The aim of this study was to evaluate the expression and the prognostic significance of the Human Epididymis Protein 4 (HE4) in urothelial tumors of the bladder.
Materials and Methods: The current study included 55 patients with a histopathological diagnosis of urothelial neoplasm obtained from transurethral resection between 2010 and 2016. The expression of HE4 was examined using immunohistochemical methods.
Results: There was 5 papillary urothelial neoplasia of low malignant potential (PUNLMP); 16 low grade non-invasive papillary urothelial carcinoma (LGUC); 7 high grade non-invasive papillary urothelial carcinoma (HGUC); 18 lamina propria-invasive urothelial carcinoma (invUC); and 9 muscle-invasive urothelial carcinomas (musc-invUC). Of the total, 20% LMP, 6.2% LGUC, 14.2% HGUC, 28.5% invUC and 33.3% musc-invUC cases were successfully stained with HE4
immunohistochemically. The overall expression of HE4 among urothelial tumors was 18.2%.
Conclusions: The Human Epididymis Protein 4 expression is proportionally higher in invasive urothelial neoplasm but the difference is not statistically significant between invasive vs noninvasive tumors. We propose that it can be used for the assessment of invasion status when the bladder muscle is not sampled.
... The proportion of K17 positive cells, however, was greater in non-papillary UC than in papillary carcinomas and the proportion of tumor cells that expressed K17 was greater in muscle invasive UC compared to non-muscle invasive UCs. K17 was also expressed in a high proportion of cells in PUNLMP, a low grade papillary neoplastic process that is thought to only rarely progress to invasive urothelial carcinoma [27]. Thus, in contrast to prior studies, which have focused on the role of K17 as a prognostic biomarker [15,17,18,28], K17 does not appear to be a consistent biomarker of urothelial tumor aggression. ...
There is a clinical need to identify novel biomarkers to improve diagnostic accuracy for the detection of urothelial tumors. The current study aimed to evaluate keratin 17 (K17), an oncoprotein that drives cell cycle progression in cancers of multiple anatomic sites, as a diagnostic biomarker of urothelial neoplasia in bladder biopsies and in urine cytology specimens. We evaluated K17 expression by immunohistochemistry in formalin-fixed, paraffin embedded tissue specimens of non-papillary invasive urothelial carcinoma (UC) (classical histological cases), high grade papillary UC (PUC-LG), low grade papillary UC (PUC-HG), papillary urothelial neoplasia of low malignant potential (PUNLMP), and normal bladder mucosa. A threshold was established to dichotomize K17 status in tissue specimens as positive vs. negative, based on the proportion of cells that showed strong staining. In addition, K17 immunocytochemistry was performed on urine cytology slides, scoring positive test results based on the detection of K17 in any urothelial cells. Mann–Whitney and receiver operating characteristic analyses were used to compare K17 expression between histologic diagnostic categories. The median proportion of K17 positive tumor cells was 70% (range 20–90%) in PUNLMP, 30% (range 5–100%) in PUC-LG, 20% (range 1–100%), in PUC-HG, 35% (range 5–100%) in UC but staining was rarely detected (range 0–10%) in normal urothelial mucosa. Defining cases in which K17 was detected in ≥10% of cells were considered positive, the sensitivity of K17 in biopsies was 89% (95% CI: 80–96%) and the specificity was 88% (95% CI: 70–95%) to distinguish malignant lesions (PUC-LG, PUC-HG, and UC) from normal urothelial mucosa. Furthermore, K17 immunocytochemistry had a sensitivity of 100% and a specificity of 96% for urothelial carcinoma in 112 selected urine specimens. Thus, K17 is a sensitive and specific biomarker of urothelial neoplasia in tissue specimens and should be further explored as a novel biomarker for the cytologic diagnosis of urine specimens.
... PUNLMP case may recur and progress. Maxwell et al., 2015 reported a progression of PUNLMP to low grade urothelial carcinoma in 9.5% patients and to high grade urothelial carcinoma in 1.6% patients [32]. In the same year, Zhang et al. reported a recurrence in 19.7% and progression up to pTa in 16.9%. ...
Background:
COX2 is a cyclo-oxygenase enzyme expressed in the tumor cells, inflammatory cells, stromal and non-epithelial cells. The study was conducted to evaluate the expression of COX2 in Urothelial carcinoma and find the association with progression and recurrence.
Methods:
The expression of COX2 was evaluated by real-time PCR and immunohistochemistry.
Results:
Gene expression of COX2 was found to be upregulated >28-fold in urothelial cancer compared to adjacent normal bladder mucosa. Inflammatory cell expression of COX2 was found in 92% cases whereas only 37% cases showed COX2 overexpression in tumor cells. Tumor cell COX2 overexpression was significantly associated with invasion and recurrence.
Conclusion:
COX2 expression is a marker of invasion, recurrence and poor survival and may have a role in predicting the cases which will benefit from additional treatment with COX2 inhibitors in urothelial carcinoma.
