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Dear esteemed researchers and colleagues,It is a great pleasure for me to announce a new journal in the field of urology: Uro, published by the MDPI group.Staying up to date is a necessity in the era of rapid technical innovation, as novel concepts are being constantly introduced into clinical practice from bench research. It is important to stay competitive and to offer patients the best and most innovative clinical approaches. At the same time, all physicians are required to keep in mind the concept of patient-centered medicine.We are, therefore, moving between the impressive acceleration of technical and pharmaceutical innovations and the patients’ desire for a tailored approach and personalized medicine.On the basis of these considerations, an easily accessible source of information is urgently required. From this perspective, Uro makes its first appearance in the world of urological and andrological journals. With great enthusiasm, the Uro editorial board is currently forming to take care of the real needs of researchers and clinically based physicians. We are working with the aim of giving readers a new, easily accessible journal that provides information on the real necessities of everyday clinical practice. In the coming months, a new modality of keeping up to date will be available in Uro.Keep up to date or perish! That’s our motto!Uro is taking its first steps, keeping in mind that translational medicine is the bridge between the pre-clinical “world” and everyday clinical practice. The final “core” aspect of Uro is the multidisciplinary approach to “border diseases”. Gynecologists, endocrinologists, surgeons, and infectious diseases specialists are some of the most common physicians involved in the management of urological patients. The multidisciplinary approach is a key component in everyday clinical practice and, moreover, in the improvement of our knowledge. In line with this aim, and to fully cover any aspect of the modern multidisciplinary approach to urological and andrological diseases, a large group of experts from many different backgrounds is enrolling for the Uro mission. Together and with the pivotal help of authors and reviewers, we aim to make the Uro a high-quality and easily accessible tool for all physicians and researchers involved in the management of patients affected by urological diseases. We hope that you will consider Uro as your privileged partner in everyday clinical practice and a source of up-to-date information and news. The author declares no conflict of interest. |
This study was undertaken to compare Fuhrman grading with World Health Organization/International Society of Urological Pathology (WHO/ISUP) grading and stereologically measured nuclear area in patients with Clear Cell Renal Cell Carcinoma (ccRCC) or Papillary Renal Cell Carcinoma (PRCC) and to evaluate the independent predictive value of Fuhrman, WHO/ISUP and stereologically measured nuclear area combined with necrosis in a series of patients with ccRCC in relation to cancer-specific survival. In all, 124 cases of ccRCC and PRCC were included. All slides were blindly scored by two trained pathologists according to the Fuhrman and WHO/ISUP grading systems. Nuclear measurements were performed on digitally scanned slides in Visiopharm® and correlated to survival. Analysis of ccRCC and PRCC cases showed that application of WHO/ISUP grading resulted in a significant downgrading of cases from G2 to G1, when comparing with Fuhrman grading. Neither of these patients experienced progression. Cancer specific survival estimates in 101 ccRCC patients showed that WHO/ISUP grading was slightly superior in predicting cancer-specific survival. Novel models included WHO/ISUP grading and mean nuclear area (MNA) each of which combined with necrosis. Both demonstrated an increased ability to predict cancer-specific survival. The study demonstrates that WHO/ISUP grading provides superior prognostic information compared to Fuhrman grading and stereologically measured nuclear area. Necrosis in combination with either WHO/ISUP grading or MNA adds additional prognostic information.Renal cell carcinoma (RCC) is a neoplasm with widely varying prognosis, from an aggressive neoplasm, with metastasis at presentation, to a slowly growing neoplasm that can be observed safely for years [1]. The overall 5-year progression-free survival rate is 70% and the cancer-specific mortality rate is 24% [2]. Numerous different prognostic markers have been investigated. However, only morphological features such as tumor size, vascular invasion, necrosis, stage and grade are routinely utilized in an effort to predict outcome [3,4].A variety of grading systems have been proposed that focuses on nuclear morphology. Of these, that of Fuhrman et al. [5], published in 1982, has achieved widespread use throughout the world in clinical routine pathology. It is a 4-tiered grading system, which is based primarily on the simultaneous assessment of nucleolar prominence, nuclear size, and nuclear irregularity. The first three grades are defined on nuclear features and the fourth grade is defined by the presence of nuclear pleomorphism, Table 1. Despite widespread usage of the Fuhrman grading system, it has become apparent that the system has a number of inherent problems, in particular those related to poor reproducibility [6,7]. At the ISUP consensus conference, a novel grading system was proposed, based on nucleolar prominence [8], Table 1. The ISUP grading system was later endorsed by the World Health Organization (WHO) and renamed as the WHO/ISUP grading system [9] with few modifications, but that the staining quality of the nucleolus should also be encompassed. The WHO/ISUP grading system should be applied to Clear Cell RCC (ccRCC) and Papillary RCC (PRCC). However, Chromophobe RCC (ChRCC) should not be graded, since neither Fuhrman or WHO/ISUP are appropriate for grading of this tumor subtype [10]. The WHO/ISUP grading system has achieved widespread usage and has now replaced the Fuhrman grading system worldwide [11].Tumor necrosis is another factor that has shown prognostic significance in several studies [4,12,13]. It occurs frequently in RCC and appears to be dependent on the histological subtype, with the highest occurrence in PRCC (32%–40%) and ccRCC (27%–32%) [4,14,15]. Delahunt et al. [4] recently proposed a modification of the current WHO/ISUP grading system incorporating tumor necrosis, Table 1. In this study, a significant difference in survival between each grade for ccRCC was demonstrated, in addition to a superior concordance index compared to ISUP grading. The ISUP Vancouver Consensus Conference on Renal Cell Carcinoma recommended to routinely include the presence or absence of tumor necrosis [8]. However, necrosis has not yet been implemented in any of the grading systems. The ability to study nuclear morphometry quantitatively is made possible by advances in computer imaging technology. Issues with lack of reproducibility, different grading systems and the subjectivity that always belongs to histological grading systems might be avoided by using a more reproducible method to assess nuclear features and thereby predicting prognosis [16,17]. Hence, it is important to acknowledge the necessity of validation of the novel grading systems in different populations, and to the best of our knowledge, only few validation studies have been performed until now [18,19]. Furthermore, with the introduction of digital pathology in many countries, it seems relevant to investigate, how stereologically assessed nuclear morphometry correlates to the different grading systems.The objectives of our study were twofold: 1) to assess interobserver reliability and agreement using the Fuhrman nuclear grading system and the WHO/ISUP grading system for ccRCC and PRCC and to correlate gradings with nuclear morphometry; 2) To evaluate the independent predictive value of Fuhrman, WHO/ISUP and stereologically measured nuclear area in relation to cancer-specific survival in patients with ccRCC and to validate novel proposed models for grading incorporating tumor necrosis.Patients nephrectomized at our institution between 2001 and 2012, who gave written informed consent and were diagnosed with PRCC or ccRCC, were included in the study. None of the patients received neo-adjuvant therapy. Files of all patients were reviewed and data regarding pathological parameters, sex, age at diagnosis and data regarding follow-up and death were obtained retrospectively. Date and cause of death were obtained from the Cause of Death Register, Denmark. The Danish Ethics Committee (permit No. S-VF.20010035, notification No. 29573) approved the experimental protocol and the study was reported to the Danish Data Protection Agency (permit No. 2008-58-0035). Paraffin-embedded tumors were sectioned and stained with hematoxylin-eosin (HE). Two pathologists reviewed independently and were blinded to all tumor slides with regard to the assessment of Fuhrman grade, WHO/ISUP grade, microscopic necrosis and subtype. Grading followed criteria listed in Table 1. Necrosis was reported, when well-demarcated foci of necrosis within tumor was observed.All slides were scanned for evaluation using a digital slide scanner, NanoZoomer 2.0-HT (Hamamatsu, Japan). Visiopharm newCAST Whole Slide Sterology software (Visiopharm, Hørsholm, Denmark) was used for calculation of nuclear area. Tumor areas were manually drawn as region-of-interest (ROI) and sample images from these were collected randomly using meander fraction-based sampling at 20 times magnification. In these images, nuclei area was calculated using the nucleator function (Figure S1).Mean nuclear area (MNA) in all sampled nuclei and mean nuclear area in the 10 largest measured nuclei (MNA-10) was calculated for each patient together with standard deviation and the number of measured nuclei in each sample. Comparisons of nuclear area across patients and pathological characteristics were performed using Student’s t-test or one-way ANOVA followed by Bonferroni’s multiple comparisons test. Correlation analysis was performed with Spearman’s rank correlation.Cancer specific survival was calculated from the date of diagnosis by imaging to the date of death from RCC or to last follow-up contact. Patients alive at the end of the follow-up, who did not experience progression during the study period, where censored at the date of last follow-up. A receiver-operating-characteristic (ROC) curve was generated for MNA and the optimal cutoff point was selected according to the point of the ROC curve closest to the top-left corner of the ROC plot. Cancer-specific survival was estimated using the Kaplan-Meier method and differences in survival among groups were calculated using log rank tests. Two novel grading systems were evaluated, one based on the 4-tiered grading classification proposed by Delahunt et al. [4], incorporating tumor necrosis in the existing WHO/ISUP grading system, the other based on dichotomization of MNA incorporating tumor necrosis.The ability of the prognostic models to predict death from RCC was evaluated by the area under a ROC curve and the c-index (Harell´s C) [20,21].The κ statistics, a measurement of reliability between observers that corrects for chance agreement, was used to evaluate the interobserver reproducibility in grading of ccRCC and PRCC between two pathologists. The maximum value for κ is 1.00, which indicates perfect agreement and 0 indicates the level of agreement expected by chance alone. Negative values indicate less than chance agreement. Agreement measures for categorical data according to Landis et al. [22] are as follows: Slight, 0.00–0.20; Fair, 0.21–0.40; Moderate, 0.41–0.60; Substantial, 0.61–0.80 and Almost Perfect, 0.81–1.00. Absolute agreement was assessed with proportions of agreement [23]. Two-sided p-values < 0.05 were considered significant. All analyses were done with STATA/SE 16.0 (StataCorp, College Station, TX, USA). The study comprised 124 patients with RCC, with either the papillary subtype 1 (n = 14), papillary subtype 2 (n = 9) or the clear cell subtype (n = 101). Table 2 presents clinicopathological data for all 124 patients included in the study and summarizes the statistical analysis for nuclear morphometry. The median follow-up was 40.6 months (range 0.9 to 136.3), during which a total of 52 (42%) patients died and 33 (27%) patients died from RCC. Forty patients (32%) experienced recurrence within follow-up with a median time to recurrence of 9.4 months. Of the 101 ccRCC patients, 35 patients (34.6%) experienced recurrence with a median time to recurrence of 9.4 months. Mean nuclei area (MNA) and mean nuclei area in the 10 largest nuclei (MNA-10) are listed in Table 2. The mean number of measured nuclei per tumor was 133 (range 13–287). Microscopic necrosis correlated with MNA (p < 0.0001) and MNA-10 (p < 0.0001), with a higher MNA and MNA-10 in patients with microscopic tumor necrosis. Neither pT stage, subtype, nor sex correlated with MNA or MNA-10. All patients were assigned a Fuhrman grade and a WHO/ISUP grade by two pathologists, blinded to clinical data. Detailed relationship between WHO/ISUP grading and Fuhrman grading is shown in Table 3 and Figure 1A. MNA and MNA-10 both correlated with Fuhrman grade and WHO/ISUP grade with a proportional increase in MNA and MNA-10 with higher grades of both Fuhrman and WHO/ISUP, Figure 1B,C. Correlation analysis revealed a significant correlation between MNA and Fuhrman as well as MNA and WHO/ISUP grade (p < 0.0001, r = 0.53 and p < 0.0001, r = 0.57, respectively).Comparison of WHO/ISUP and Fuhrman grades demonstrated a significant downgrading upon WHO/ISUP grading (p < 0.0001). In particular, only five patients were given the grade G1 (4%) according to Fuhrman grading, whereas 26 patients were graded G1 according to WHO/ISUP (21%). No significant difference in MNA was seen between the grades of Fuhrman and WHO/ISUP (Figure 1D). Interobserver κ-value for Fuhrman was 0.34, SE = 0.059 (Fair) and for WHO/ISUP 0.48, SE = 0.055 (Moderate). Interobserver κ-value for microscopic necrosis was 0.60, SE = 0.09 (Moderate). The proportion of agreement for Fuhrman grade and WHO/ISUP grade was 72.6% (95% CI: 63.8%–80.2%).Figure 2A depicts the receiver operating characteristic (ROC) curve characterizing the ability of MNA to predict death from RCC (Cancer Specific Survival), which was used to generate the optimal cut-point, as shown by the dashed vertical line in Figure 2B. The cut-off value of 35.75 μm2, as determined by the ROC curve, had a sensitivity of 93.9% and a specificity of 47.3% in predicting death from RCC.Kaplan–Meier survival curves for 101 cases with ccRCC morphology according to Fuhrman grading, WHO/ISUP grading and MNA are shown in Figure 3, Figure 4 and Figure 5. None of the patients with grade 1 tumors developed tumor recurrence or metastatic disease during the follow-up period, Figure 3 and Figure 4. The division of MNA into a two-tiered grading system could significantly separate patients with good or poor prognosis, Figure 5. However, in the good prognosis group, five patients experienced progression in disease.As demonstrated by the c-indexes, the WHO/ISUP grading system contained greater predictive ability compared with the Fuhrman grading system and the stereologically measured MNA (c- indexes of 0.74 versus 0.68 and 0.70, respectively), Table 4. Proposed novel grading models, incorporating necrosis with either MNA or WHO/ISUP, resulted in slightly greater predictive ability (c-indexes of 0.76 and 0.75, respectively). In this study, we investigated the prognostic significance of the Fuhrman grading system, the WHO/ISUP grading system, and the correlation of nuclear morphometry to clinical outcome together with two novel, modified grading systems in ccRCC. We demonstrated that the WHO/ISUP grading system is superior in predicting cancer-specific survival. Modified groups, combining either WHO/ISUP or MNA with necrosis, were only slightly superior to WHO/ISUP grading alone. Interobserver reliability calculated with kappa statistics was moderate for the WHO/ISUP grading system and fair for the Fuhrman grading system.The Fuhrman grading system was published in 1982 and the study behind has later been criticized for having major limitations, such as small number of patients, limited follow-up time, and no distinction between the different morphological subtypes of RCC. Yet, the Fuhrman grading system has achieved great popularity and is still used by many pathologists today [7]. Over the years, other issues have arisen when validation has been pursued, including poorly defined criteria for nuclear pleomorphism and difficulties in assessing nuclear diameter objectively. There is no recommendation of the relative importance of each of the parameters (nuclear diameter, nuclear shape, and nucleolar prominence) and no guidance on how to stratify between them, when contradictory results are obtained. Furthermore, lack of reproducibility within studies with reporting of significant variation in the distribution of the Fuhrman grades and variation in association to outcome are other important issues. Some studies suggest limited prognostic significance unless grades are combined for statistical analysis [24,25]. This has led pathologists to attempt to grade only on the basis of nucleolar prominence, which does not conform to the grading criteria of the Fuhrman system [6]. The WHO/ISUP system has now, to some extent, replaced the Fuhrman grading system. Only a few studies have validated the novel WHO/ISUP system in comparison to Fuhrman grading [13,18,19,26]. These studies demonstrated a superior predictive ability of the WHO/ISUP compared to the Fuhrman grading system. In our series, we showed that grade 1 tumors according to both the WHO/ISUP grading system and the Fuhrman grading system were associated with an excellent prognosis, with no cases showing cancer progression. There was a significant separation in outcome between grades 1 and 3 according to both grading systems. However, grade 2 showed overlap of survival curves and we could not demonstrate a clear separation by WHO/ISUP grading. This could indeed be due to a smaller case number and not reflect a true problem of the grading system, since other larger studies did not report this [18]. Dagher et al. demonstrated that grading according to the WHO/ISUP resulted in a relative downgrading of cases as compared with Fuhrman grading. This was explained by the criteria of the WHO/ISUP, which bases the first three grades on nucleolar features. We could demonstrate a similar downgrading of cases when applying the WHO/ISUP grading system. Since WHO/ISUP grading demonstrated a significant downgrading of cases from G2 to G1, of which none of these experienced recurrence or metastatic disease, it seems that this grading system is slightly better at separating the group with excellent prognosis from the intermediate group.In the present study, Fuhrman nuclear grading and WHO/ISUP grading was carried out by two observers. There was a fair agreement between them with a kappa value of 0.34 for Fuhrman nuclear grading and a moderate agreement with a kappa value of 0.48 for WHO/ISUP grading. Clearly, there is a subjectivity in nuclear grading, using either the Fuhrman grading system or the WHO/ISUP grading system, that might be avoided when replaced by quantitative morphometric approaches which evaluate nuclear features. There has been significant research investigating the usefulness of nuclear morphometry to provide information regarding prognosis in patients with RCC [16,27]. MNA has been considered to be one of the most valuable prognostic factors among several morphometric parameters. In the literature, the proposed cut point for dichotomization of patients with good and poor prognosis differs within a range of 32 to 39 µm, which could reflect a true difference, but could also be explained by differences in fixation times or preparation methods. Nevertheless, the identified cut point of MNA in our study is within this range. An isolated assessment of only one quantitative feature, such as nuclear area, may not suffice to describe nuclear abnormalities and the combination of several features may be required in order to give an accurate prediction of prognosis, as concluded by Montironi et al. [28]. Other suggested morphometric parameters are, among others, nuclear area index (NAI), nuclear perimeter, nuclear roundness factor, major and minor diameter, and nuclear form factor [17,27,29]. Stereological measurements of nuclear size are time- and labor-consuming when they, as in this case, are performed by applying the Nucleator function in Visiopharm. Whether the introduction of worldwide digital pathology makes such quantitation quicker and easier is not yet possible to establish. Our work has shown that both Fuhrman and WHO/ISUP grading correspond with increasing mean nuclear size (MNA). The objective, quantitative, and reproducible measurement of nuclear morphometry might be useful as a supplement to the histopathological grading, but the WHO/ISUP grading is significantly easier to applicate, less time-consuming, and provides a reasonable reliability. Another important issue is the prognostic significance of tumor-related necrosis, which has also been emphasized in many other studies [4,13,30]. However, there seems to be conflicting terminology to describe necrosis. Delahunt et al. describe RCC tumor necrosis as either thrombo-embolic infarction, resulting in tumor coagulative necrosis or as a specific form of necrosis or tumor-related necrosis [31]. Dagher et al., define tumor-associated necrosis as well-demarcated foci of necrosis within the tumor [12]. The ISUP Vancouver Consensus Conference on Renal Cell Carcinoma recommend that the presence or absence of macroscopic and microscopic necrosis should be routinely reported in pathology reports [8]. However, since tumors may be associated with two separate forms of necrosis and thereby two different pathogenic pathways leading to necrosis, confusion relating to how to report necrosis could arise. Unfortunately, none of the two reference groups recommend a methodology for interpreting the prognostic significance of these two types of necrosis [8,9] In this study, microscopic necrosis was reported in accordance with Dagher et al. [12]. Foci of hemorrhage, fibrosis, or hyalinization should not be encountered as tumor necrosis. The prognostic significance of tumor necrosis applies only to ccRCC and has not been demonstrated for the papillary RCC [9].It is important to acknowledge the limitations of this study. First, the results are based on a single-center retrospective study and must be verified in larger, prospective multi-center studies. Second, only the mean nuclear area was reported, and other nuclear features could be relevant to investigate. However, the strengths of our study include separation of renal cell carcinomas into subtypes, subjecting only ccRCC to prognostic evaluation, and inclusion of necrosis as a prognostic factor. In conclusion, our study did not demonstrate a clear separation of cancer-free survival curves between the four groups of either the WHO/ISUP system or Fuhrman grading. The WHO/ISUP grading system was slightly superior in predicting cancer-specific survival than the Fuhrman grading system and Mean Nuclear Area. Furthermore, a downgrading of cases from G2 to G1 according to WHO/ISUP in comparison with Fuhrman grading resulted in a separation of patients with an excellent prognosis. Combining necrosis with either the WHO/ISUP grading system or MNA enhanced the predictive ability. The following are available online at https://www.mdpi.com/2673-4397/1/1/2/s1, Figure S1: Illustration of the Nucleator function in Visiopharm, measuring the area of the nucleus in ccRCC.Conceptualization, N.M and M.R.; methodology, N.M. and M.R.; formal analysis, M.R. and O.G.; investigation, N.M, M.R., O.G., and B.E.; resources, N.M.; writing—original draft preparation, M.R.; visualization, M.R.; supervision, N.M., O.G., and B.E. All authors have read and agreed to the published version of the manuscript. This research received no external funding.The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of The Danish Ethics Comittee (permit No. S-VF.20010035, notification No. 29573, date of approval: 03.05.2011).Informed consent was obtained from all subjects involved in the study.The data presented in this study are available on request from the corresponding author. The data are not publicly available due to restrictions of privacy.The authors declare no conflict of interest.(A). Comparison of Fuhrman and WHO/ISUP grading systems in 124 patients with clear cell or papillary renal cell carcinoma. (B–D). Comparison of Fuhrman grade and WHO/ISUP grade with Mean Nuclear Area (MNA) and Mean Nuclear Area in the 10 largest nuclei (y-axis).(A) Receiver operating characteristics (ROC) curve characterizing the ability of the Mean Nuclei Area (MNA) to detect patients who die from RCC (CSS). The cut-off value of 35.75 μm2 had a sensitivity of 93.9% and a specificity of 47.3% in predicting death from RCC. (B) Histogram depicting Mean Nuclei Area and the selected cut-off value.Cancer specific survival by the four-tiered Fuhrman grading system for 101 patients with ccRCC (p = 0.008).Cancer specific survival by the WHO/ISUP four-tiered grading system for 101 patients with ccRCC (p = 0.002).Cancer specific survival in ccRCC patients with tumors with an MNA of >35.75 μm2 (represented by the red line) vs. others (p = 0.0006).Overview of different grading systems.Correlation of nuclear area with patient characteristics.* Students t-test. ** One-way ANOVA followed by Bonferroni’s multiple comparisons test. Abbreviations: MNA; mean nuclear area, MNA-10; mean nuclear area in the 10 largest nuclei, SD; standard deviation. RCC; Renal cell carcinoma, ccRCC; Clear Cell RCC.Relationship between Fuhrman grading and WHO/ISUP grading.Abbreviations: WHO/ISUP; World Health Organization/International Society of Urological Pathology.Comparison of AUC-ROC and C-indexes between different prognostic models.Abbreviations: MNA; mean nuclear area, WHO/ISUP; World Health Organization/International Society of Urological Pathology, AUC-ROC; Area Under the ROC-Curve. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
The quality of life (QoL) concept now includes new aspects related to patients’ well-being because QoL has become more of a personal perception than an an objective and measurable entity. Here, we discuss the principal aspects of QoL-related aspects in urology and andrology by using a narrative review. Some aspects concerning the QoL are essential when managing uro-andrological patients. The aim of treatments should not only include the absence of disease or symptoms relief but also the improvement of a patient’s QoL with regard to his/her internal status and relationship with others. In this sense, any therapeutic approach should be based on the patient’s perspectives and not only on the instrumental and laboratory findings. Finally, we discussed the role of a patient’s sexual partner adding an extra dimension to the patient-centerd approach as part of the QoL concept in andrology.Due to the improvements in medical care such as technical innovations, new drugs and new insights into the pathophysiology of urological diseases, the average life expectancy of patients has increased considerably in the last few decades [1]. However, improvement in life expectancy is not always linked with an improvement in quality of life (QoL). For this reason, all health-care practitioners are advised to pay attention to the QoL of urological patients [2]. In an editorial in the Annals of Internal Medicine, Elkington states, “What every physician wants for every one of his patients old or young, is not just the absence of death but life with a vibrant quality that we associate with a vigorous youth. This is nothing less than a humanistic biology that is concerned, not with material mechanisms alone, but with the wholeness of human life, with the spiritual quality of life that is unique to man” [2,3]. In this sense, all urologists and andrologists should improve their knowledge about QoL and the tools for QoL measurement. In doing so, urologists and andrologists can pioneer these ethical and professional perspectives in their respective medical fields. In everyday clinical practice, patient-centered medicine and patient engagement has a key role in improving the patient-doctor alliance and patients’ adherence to the treatment. The aim of the present paper is to give a narrative review of QoL-related aspects in urology and andrology in order to provide the reader with some simple tools to use in everyday clinical practice.This narrative review aims to update QoL aspects in the urological and andrological settings, focusing on attitudes towards the concept of QoL and its implementation in everyday clinical practice.A search was performed in PubMed, Cochrane CENTRAL, and Scopus databases for relevant publications by using the following terms "quality of life" AND “urology" OR "andrology". Two authors (TC and PV) independently reviewed the selected articles. Any disagreements among reviewers were resolved through discussion and consensus. All references cited in relevant articles were also reviewed and analyzed. The filters used included the English language. Even if this search was planned as a narrative review, our search was performed in line with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) and the recommendations of the European Association of Urology guidelines (EAU) for conducting systematic reviews and meta-analyses [4,5]. Our research identified 2403 articles of potential interest. After the first screening round, 196 articles were considered eligible for inclusion in our narrative review. Most articles (185) were published during the last 20 years. Only 5 articles were published between 1990 and 1995. In 1947, the World Health Organization (WHO) defined QoL as a “state of complete physical, mental, and social well-being, and not merely the absence of disease and infirmity” [6]. In 1995, the WHO definition evolved as follows: “Individuals’ perceptions of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards, and concerns. It is a broad ranging concept incorporating in a complex way the persons’ physical health, psychological state, level of independence, social relationships, personal beliefs, and their relationships to salient features of the environment" [7].For long, this definition has been the most important and influential definition, but the concept of QoL has changed during recent years. Successively, the concept of health-related quality of life (HR-QoL) was introduced and defined as “how well a person functions in their life and his or her perceived wellbeing in physical, mental, and social domains of health” [5,6,8,9]. In other words, HR-QoL could be defined as: “Quality of life is an all-inclusive concept incorporating all factors that impact upon an individual’s life. Health-related quality of life includes only those factors that are part of an individual’s health” (Torrance [8]). Nowadays, the QoL concept includes other aspects related to a patient’s well-being. Many authors placed a greater emphasis on people’s subjective perceptions of the most important features of their lives, considering the QoL more of a personal perception and not only an objective and measurable entity. In this sense, Wenger et al. in 1984 defined QoL as “an individual’s perceptions of his or her functioning and well-being in different domains of life” [10]. This new definition of QoL takes into account what a patient thinks about his/her internal state, as well as their relationship with other people. QoL should be considered as a rich interplay and balance between how people see their internal state and how people see their relationships with other people (e.g., partner, friend, etc.). This new concept of QoL has important consequences for the management of patients affected by urological and andrological diseases. Any therapeutic approach should be considered in the light of this new and extended definition [11]. In this sense, the aim of treatment was not only to promote the absence of the disease or symptoms relief, but to improve patients’ QoL both in terms of his/her internal status and the relationship with other people [2,11]. The QoL then becomes a two-dimensional entity: an internal dimension (patients’ feel good about her/himself) and an external dimension (patients’ feel good about others) [2].Figure 1 shows the interaction between internal and external dimensions when determining patients’ QoL.On the other hand, some authors described four broad health dimensions that summarize the specific QoL components (Figure 2) [2,12]:Physical health (somatic sensations, disease symptoms)Mental health (positive sense of well-being, nonpathological forms of psychological distress or diagnosable psychiatric disorders)Social health (aspects of social contacts and interactions)Functional health (self-care, mobility, physical activity level and social role functioning in relation to family and work).Physical health (somatic sensations, disease symptoms)Mental health (positive sense of well-being, nonpathological forms of psychological distress or diagnosable psychiatric disorders)Social health (aspects of social contacts and interactions)Functional health (self-care, mobility, physical activity level and social role functioning in relation to family and work).The Dijkers’s model is one of the most important examples of this concept because it summarizes all patient-related aspects that impact QoL [2,13].Figure 3 shows a simplified representation of the Dijkers’s model.We argue that the Dijkers’s model should also be adopted in the urological and andrological settings [13]. Indeed, uro-andrological diseases have a two-dimensional feature:The objective dimension (outsider)The subjective dimensions (insider)The objective dimension (outsider)The subjective dimensions (insider)In the objective dimension (outsider), we found that all observable life conditions were measurable and influenced by the relationship with other people (e.g., partners, friends) [14]. In this dimension, we found all physical functioning conditions. In the subjective dimension, we found all aspects referring to the patient’s perceptions, such as previous personal experience and perspectives.This new concept of QoL perfectly describes patients’ expectations to any given treatment. Urological treatments are not only asked to resolve the clinical problem but improve or maintain patients’ QoL, where possible. For instance, the maintenance of urinary continence and erectile function are, together with cancer free-survival, the most important goals in the management of patients affected by prostate cancer [15]. Even if this concept seems easy to understand and consider in everyday clinical practice, the patient perspective is not always taken adequately into account [11]. This especially may occur in the management of non-oncological disease. Recently, Cai et al. demonstrated that, during management patients, affected by lower urinary tracts symptoms (LUTS), the sexual function, and sexual quality of life should be analyzed in depth because sometimes patients report LUTS instead of sexual symptoms because they feel embarrassed [16]. In this paper, Cai et al. demonstrated that an appropriate and useful therapeutic approach should be based on the patient’s perspectives and not only on the instrumental and laboratory findings. The extended definition of QoL has recently increased interest in everyday clinical practice and, for it, QoL is one of the most important endpoints included in the guidelines and recommendations of many medical societies.The recent evolution of the concept of QoL has positively changed the doctor–patient relationship. An increasing number of published papers demonstrates increasing interest in the concept of QoL. Over the last 5 years, about 50% of published articles on QoL (1032 out of 2403) were in the field of urology, thus demonstrating a particular interest of the scientific urological community. Schmick et al. reported, in a large survey among German urologists, that their attitude towards QoL was mainly positive, and most urologists considered QoL as a necessary part of their everyday clinical practice, even if urologists’ knowledge concerning QoL assessment, analysis, and interpretation was limited [17]. Moreover, they highlighted an important aspect that we discuss in the next section: the use of patient-reported outcome measures (PROMS) in QoL measurement [17]. Stewart considered QoL as a core element in the doctor–patient relationship [18]. She underlined that important aspects of the doctor–patient relationship are “the integration of these concepts of disease and illness with an understanding of the whole person in context, that is, an awareness of the multiple aspects of the patient’s life such as personality, developmental history, life cycle issues, the proximal context, such as family, and the distal context, such as community and physical environment” [18]. According to Stewart, the following components are essential in a patient-centered clinical approach:-Exploring both disease and the patients’ illness experience-Understanding the whole person-Finding common ground-Incorporating prevention and health promotion-Enhancing the patient-doctor relationship-Being realistic [18].Exploring both disease and the patients’ illness experienceUnderstanding the whole personFinding common groundIncorporating prevention and health promotionEnhancing the patient-doctor relationshipBeing realistic [18].The concept of a patient-centered approach was recently introduced in urology with special focus on improving patients’ adherence to treatment and patients’ QoL. In 2018, De Nunzio demonstrated a dramatically low drug adherence and satisfaction with medical treatment among LUTS patients [19]. He highlighted the need for a patient-centered approach that aimed to improve drug adherence and other unmet needs in this area, such as adverse effects on sexual function management and the risk of disease progression [19]. No other substantial contributions in the urological or andrological field have been reported so far, even though a patient-centered approach is likely to benefit many patients in these fields. In particular, there is room for improvement in the andrological setting by increasing involvement of the patient’s sexual partner. The patient’s sexual partner adds an extra dimension to the patient-centered approach as part of the QoL concept in andrology.Figure 4 shows this new concept of andrological patient aspects influencing QoL: the interaction between “insider and outsider view of the patient” and “insider and outsider view of the partner”, as well as their interaction with the outsider view of the “couple”.The partners’ sexual interest is important for a patient to recover the sexual function both in non-oncological and oncological diseases [20]. In a review article, Guercio et al. showed that mental health, physical health, quality of interpersonal communication, and patient-perceived partner support are the most important predictors of sexual satisfaction both for patients and partners in the post-prostatectomy period, demonstrating the need for further research on this topic [21].On the other hand, cultural or religious schemata could limit the usefulness of treating patients as ’couples.’ In this sense, Asian, African, or Middle Eastern origin patients may withhold such information for cultural reasons, and lesbian, gay, bisexual, and transgender (LGBT) partners may not be so forthcoming in their disclosures for fear of stigmatization [22]. All urologists and andrologists are asked to pay particular attention to patients’ sexual orientation in order to improve adherence to the therapeutic approach. Future research in this area is needed. The definition and assessment of QoL should be conducted considering various cross-cultural and religious dimensions. Several factors affecting the QoL definition are mainly determined by cultural or religious schemata, as is apparent in folk illnesses [23,24]. In urological and andrological setting, these aspects should be considered due to the fact that some diseases affect the sexual function or genitalia.Due to the expansion of the concept of QoL and the raising interest for QoL in everyday clinical practice and research, there is a need for reproducible and accurate tools for its measurement. In the world of business management, there is a mantra that guides all decisions: What is not measured cannot be improved. In the last century, Lord Kelvin said that “What is not defined cannot be measured. What is not measured cannot be improved. What is not improved is always degraded” [25]. In healthcare, this principle is of crucial importance. Health professionals rely on empirical evidence to develop new treatments, optimize decision-making, save more lives. and improve patients’ quality of life [26]. Measuring a patient’s well-being after a treatment is fundamental to understand the effectiveness of that intervention [27]. QoL is not directly measurable and needs to be translated to indicators of its constituents and domains to be quantified [27]. General health perception, psychological well-being, and functioning are essential dimensions of QoL while symptoms and vitality are important causative variables [28]. Today, we have hundreds of QoL measures, many of which have been developed in recent years using generic measures that are applicable to most people, as well as specific tools for QoL measurement in people with specific clinical conditions [28]. Examples of QoL measures include the Beck Depression Inventory (BDI), the Sickness Impact Profile (SIP), and the 36-item Short Form Health Survey (SF-36) [28] (Table 1). These measures cover a wide range of aspects of life that can be adversely affected by ill health, such as physical functioning, emotional well-being, and ability to undertake work and social activities [29,30]. In a review article about the role of QoL in urological non-oncological and oncological diseases, Heldwein et al. underlined that QoL outcome measurements have become an important endpoint in urology, allowing urologists to better understand how each disease differs in different individuals [11]. Moreover, they reported that major urology society guidelines now recommend using self-report questionnaires for the most commonly used QoL measurement tools in clinical settings.PROMs has become a valuable tool for use in everyday clinical practice as well as in research [11]. PROMs is a fundamental instrument to learn and understand the before and after condition of patients, and to put patients’ needs and preferences at the center of their care [31]. Several studies have used PROMs in a variety of generic measures of QoL to evaluate the efficacy of a treatment. PROMs is different than PRO (patient reported outcomes), which is a generic term that refers to the perspective of the patient themselves [31]. In an urological setting, the use of PROMs is common, especially when evaluating the outcome of oncological disease management. Several reviews have evaluated the scientific or psychometric properties of existing PRO questionnaires being used for patients diagnosed with prostate cancer [32]. However, even if there are many published studies that use PROMs to evaluate the QoL in prostate cancer patients, these instruments strongly focus on urinary, sexual, and bowel symptoms/function. All questionnaires include some items with a more subjective element to determine the extent to which men are concerned or bothered by a particular symptom [30]. However, no instrument includes the full range of items necessary to assess HRQL in terms of the subjective impact of physical, mental, and social aspects of prostate cancer [32].In andrological and urological setting, no specific assessment tools for QoL of the patients’ sexual partner have been developed and validated. The Female Sexual Function Index (FSFI) was created only to assess female sexual function. A specific tool for assessing QoL of the sexual partner, independently from the partner sexual orientation, is urgently required [33]. The QoL concept now includes new aspects related to a patient’s well-being, particularly people’s subjective perceptions of the most important parts of their lives. QoL has become more of a personal perception and not only an objective and measurable entity. The aim of treatments is not only the absence of the disease or symptom relief but also to improve a patient’s QoL for his/her internal status and relationships with other people.Any therapeutic approach should be based on patients’ perspectives rather than instrumental and laboratory findings. A patient’s sexual partner adds an extra dimension to the patient-centered approach as part of the QoL concept in andrology.Measuring a patient’s well-being after treatment is fundamental to understanding the effectiveness of that intervention. QoL is not directly measurable and needs to be translated to indicators of its constituents and domains to be quantified.Presently, among the many extant QoL measures, PROMs constitute a significant advance as a tool for use in the routine clinical management of individual patients and in clinical research.Conceptualization, T.C.; research, T.C. and P.V.; writing—original draft preparation, T.C.; writing—review and editing, T.E.B.J. All authors have read and agreed to the published version of the manuscript.The authors declare no conflict of interest.The interaction between internal and external dimensions when determining patients’ quality of life (QoL).The four broad health dimensions that summarize the specific QoL components.A simplified representation of the Dijkers’s model.The new concept of andrological patient aspects influencing QoL: the interaction between “insider and outsider view of the patient” and “insider and outsider view of the partner”, as well as their interaction with the outsider view of the “couple”.QoL assessment tools.Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
Plasmacytoid variant of urothelial carcinoma is a rare subtype of urothelial carcinoma that has poor prognosis. We describe two cases of patients with the plasmacytoid variant of urothelial carcinoma (PVUC) who had initial response to neoadjuvant chemotherapy followed by radical cystoprostatectomy and lymph node dissection but presented with early relapse and disease progression manifesting with intestinal obstruction and peritoneal carcinomatosis. Tumor genomic sequencing revealed mutations and alterations in ARID1A, CDH1, PIK3CA, RB1 loss, and TERT promoter, as well as tumor mutational burden of 10 Muts/Mb treated with pembrolizumab with a minimal response. A further review of the literature regarding this rare variant is discussed here. The plasmacytoid variant of urothelial carcinoma (PVUC) makes up a rare subtype of urothelial cancers. This aggressive variant accounts for an estimated less than 5% of invasive cancers originating from the urothelial tract of the bladder that, in turn, account for 90% of diagnosed primary bladder cancers [1,2]. Variants of the urothelial carcinoma display morphologies distinct from usual or typical patterns of invasive urothelial carcinoma. The plasmacytoid variant is characterized by tumor cells that resemble plasma cells and/or monocytes, as well as a variable number of single cells with the appearance of signet ring cells [3]. The prognosis of this variant is often poor due to the commonly advanced disease presentation upon diagnosis warranting aggressive treatments [1,4,5].A 61-year-old Caucasian male presented with dysuria, with a 40-pack-years of smoking history, coronary artery disease, hypertension, and chronic gastroparesis. However, given symptoms of increased pelvic pain, urinary urgency, and hematuria, a cystoscopy was performed and showed a bladder tumor that was treated with primary transurethral resection of bladder tumor (TURBT). The pathology revealed high-grade PVUC invading the lamina propria and muscularis propria with viable cells in both layers (Figure 1). After also experiencing flank pain, an ultrasound and a CT scan were performed, revealing bilateral hydronephrosis for which nephrostomy tubes were placed and bladder wall thickening, increased renal echogenicity, and seminal vesicle calcifications were found (Figure 2). He completed three cycles of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC), which was complicated by multiple gastrointestinal (GI) symptoms of nausea, vomiting, resultant hypokalemia, and cytopenia, but he was able to successfully undergo definitive robot-assisted laparoscopic radical cystoprostatectomy, bilateral lymph node dissection with bilateral ureterolysis, and neobladder continent urinary diversion with ileum. The final pathology revealed ypT2N0Mx PVUC bladder cancer. While the resolution of bilateral hydronephrosis was seen initially, he developed persistent GI symptoms ten months later that warranted an eventual cholecystectomy. Regardless, symptoms of nausea, vomiting, and pain persisted, which necessitated obtaining a CT scan that showed changes that included recurrent bilateral hydronephrosis and bowel loop thickenings suggestive of the development of enteritis; a small bowel follow-through revealed intestinal obstruction (Figure 3C). A surgical exploratory laparotomy revealed multiple tumor deposits, and a thick, fibrous, mass-like tissue adhering the transverse colon to the anterior abdominal wall was dissected. However, given the extent of the adhesions and tumor deposits occurring diffusely in the abdomen and pelvis, it was elected to not remove the affected small bowel and instead bring up an end-ileostomy to relieve his obstruction. The pathology from these biopsies showed metastases of the high-grade PVUC with infiltrating plasmacytoid and signet ring cells in the small bowel and omentum with immunostaining positive for GATA-3, CD138, CK20, and CK7 (Figure 3). Further staging revealed mediastinal lymphadenopathy on a chest CT scan. Further genomic sequencing using FOUNDATIONONE® CDX genomic profiling showed alterations in ARID1A Q1095fs*10, CDH1 T364fs*3, PIK3CA M10431, RB1 loss, and TERT promoter −124C>T, as well as a tumor mutational burden of 10 Muts/Mb and a stable microsatellite status (MS-stable). He was only able to receive one dose of the PD-1 inhibitor pembrolizumab but with progressive physical and functional decline, as well as gastrointestinal complication symptoms; he declined further treatment and proceeded with hospice. He passed away two years and four months after his initial diagnosis.Case 2 is a 71 y/o male who presented with prostatic hyperplasia symptoms and acute renal insufficiency. Initial imaging showed bilateral hydronephrosis and bladder calcifications. He underwent TURP and TURBT, which revealed high-grade urothelial carcinoma with plasmacytoid and micropapillary features. CT staging showed a markedly thickened and nodular wall of the urinary bladder and calculus (Figure 4), which was consistent with bladder malignancy (suspicious for a diffuse infiltrating tumor) and an abnormal right ureteral dilation with wall thickening and enhancement suspicious for tumor involvement in the right ureter, as well as bilateral pelvic sidewall and retroperitoneal lymphadenopathy. He received chemotherapy with gemcitabine and cisplatin for six cycles with good partial response and ultimately underwent radical cystoprostatectomy, ileal diversion, and lymph node dissection with pathology that revealed high-grade urothelial carcinoma with a plasmacytic variant signet ring and micropapillary features with bulky residual disease pT4pN2Mx. Immunopathologic staining showed +CK20, p53, HER2+ IHC stains, negative PSA, and PD-L1 staining. Sequencing results showed ERBB2 amplification. However, he had ongoing gastrointestinal symptoms of nausea and vomiting, which led to further endoscopies that revealed peritoneal carcinomatosis. He received several cycles of pembrolizumab, and though initial symptom stabilization was seen, further progression ensued and hospice ultimately engaged.PVUC is a rare and aggressive variant that only accounts for a smaller proportion of diagnosed urothelial bladder cancers. It is predominantly observed in males above 55 years of age and is often associated with higher lymph node involvement, locally advanced tumors, and muscle-invasive disease, and it is more likely to be diagnosed at higher stages compared to pure urothelial carcinomas (UCs) [5,6]. The prognosis of urothelial cancers of the plasmacytoid variant is often poor, with high local recurrence rates and a decreased overall survival (OS); studies have shown a five-year OS of 27% for PVUC compared to 45% for pure urothelial cancers [2]. Initial presentation is typically similar to urothelial bladder cancers, often with gross or microscopic hematuria [7] and other urinary obstructive or irritative symptoms. The histological presentation of the plasmacytoid variant is characterized by atypical cells—specifically plasma-like cells with ample eosinophilic cytoplasm and displaced nuclei that may contain vacuoles or form signet rings often composing at least 50% of the tumor. Plasmacytoid variants can express the plasma cell marker CD138 (syndecan-1), and E-cadherin is often down regulated or negative, helping the diffuse permeation of the tumor cells [8]. Other products that may be found by the immunohistochemistry of PVUC include GATA3, p63, CK7, CK20, S100P, and protein-15 [9]. In our present case, tumor cells were initially found during the TURBT of the bladder, and while successful surgery was done with cystoprostatectomy and lymph node dissection with ileal diversion, recurrence occurred later on with metastasis to the omentum and the small bowel, as well as intraperitoneal spread. Immunohistochemical staining was utilized to confirm the origin of the metastasis and was positive for GATA3, CK7, CK20, and CD138, further confirming the metastasis of the PVUC to the omentum and small bowel in this patient. The results of genomic sequencing in these rare variants likely explains the poor prognosis and the potential for peritoneal carcinomatosis in part. Studies have shown the significant overexpression of CDH1 mutations in the plasmacytoid variant (50%) compared to pure UC (2%) [10]. The CDH1 mutation leads to the loss of E-cadherin that is often found on immunohistochemical staining. This loss of E-cadherin can lead to the enhanced cellular migration of the tumor cells and the potential for the peritoneal pattern of disease seen in PVUC, and it may also contribute to a poor prognosis [11]. The loss of RB, a tumor suppressor protein, is seen in various malignancies but has been observed to contribute to the progression of high-grade invasive cases of bladder cancer via various pathways [12]. A retrospective study on 81 patients with UC found ARID1A expression to have an inverse correlation with the stage of UC in both conventional pure UC and variants. ARID1A expression was also found to be lower in variants, which generally have a worse prognosis compared to conventional UC. Its encoded protein is involved in cellular proliferation and tumor suppression, possibly explaining the higher staging and poorer prognosis found in this study [13].In a particular study that looked at 10 cases of PVUC that were subjected to genomic sequencing, nine had a mutation in at least one gene from commonly involved genes including TERT, FGFR3, PIK3CA, TP53, HRAS, KRAS, ERBB2, CDKN2A, MET, MLL, and VHL. PIK3CA mutations do not seem to occur specifically based on a particular stage or type and can be found in tumors of all stages of bladder cancer. TERT promotor mutations are the most common mutations found in UCs, and in a retrospective study of 10 PVUC cases, six were found to have TERT promotor mutations. These commonly mutated genes have diagnostic potential and have been suggested for diagnostic panels for UC [14]. Genomic sequencing on our present case showed alterations in ARID1A, CDH1, PIK3CA, RB1 loss, and TERT promotor, as well as a high tumor mutational burden. The peritoneal carcinomatosis of this patient may have been contributed to by some of these gene mutations, especially CDH1. The finding of mutations in ARID1A, CDH1, and RB1 loss align with the poor prognosis of the case as well. In addition, mutations in PIK3CA have been found to be potent oncogenic drivers in urothelial cancers [15]. While the patient in Case 2 also had sequencing findings with the ERBB2 mutation, it may have been the concomitant micropapillary component that conferred this genomic sequencing finding [10].Given the rarity of plasmacytoid variants, treatment has not been uniformly defined. However, chemotherapy, which has been historically used for conventional or pure urothelial cancers, has often been used with relatively good success in PVUC, although the durability of response is often lacking [6]. However, a few reports have shown inconsistent benefit from the use of neoadjuvant or adjuvant chemotherapy [16,17,18], often used whenever possible, followed by consolidative surgery as the main therapeutic option of choice. In a retrospective study of 31 patients with PVUC, pathological down-staging was found in 80% of patients with resectable disease compared to the upstaging found in most patients who received surgery up-front. Despite the achieved pathological down-staging, recurrences still occurred in a majority of patients, most commonly in the peritoneum [6]. Given its often higher stage at diagnosis, those with PVUC are more likely to undergo more aggressive multimodality treatments with both chemotherapy, either adjuvant or neoadjuvant, and surgery. Chemotherapy regimens that are commonly utilized include MVAC, gemcitabine and cisplatin (GC), and a mixture of ifosfamide, doxorubicin, and gemcitabine. While immunotherapy has gained a major role in the treatment of conventional urothelial cancers [19], little is known about possible efficacy in plasmacytoid urothelial variants. In our particular case series, where both patients received pembrolizumab, there were no discernible responses, thus highlighting the need for alternative, more active agents in this aggressive variant.The plasmacytoid variant of urothelial carcinoma often confers a dismal prognosis with possible links to genomic mutations involving CDH1 and the loss of E-cadherin that explains its propensity for intraperitoneal spread. While surgery is often used for early localized disease, systemic therapy is often required for more advanced disease presentation. Treatment with chemotherapy, while initially effective, often does not lead to durable responses. The use of checkpoint inhibitors appears to have limited responses. This poses an area of increased unmet need for the discovery of novel therapeutics for this aggressive variant of urothelial cancer. Conceptualization, J.B.A.-C.; formal analysis, A.E., W.L., S.M.-L., S.C., J.B.A.-C.; investigation, resources, and data curation, A.E., W.L., S.M.-L., S.C., J.B.A.-C.; writing—original draft preparation, writing—review and editing, A.E., W.L., S.M.-L., S.C., J.B.A.-C.; All authors have read and agreed to the published version of the manuscript.This research received no external funding.Patient consent was waived due to subjects being deceased.We would like to acknowledge the David Wohlscheid Fund for administrative support.J.B.A.-C. reports consultant fees from Merck, Immunomedics, EMD Serono, Pfizer, but not related to this manuscript. All other authors declare no conflict of interest.Radical bladder cystoprostatectomy specimen: residual invasive carcinoma (<1% viable tumor cells in the tumor bed), focally invasive into muscularis propria, with ypT2a pN0. (A) Viable tumor cells in lamina propria (100×); (B) viable tumor cells in lamina propria (200×); (C) viable tumor cells in muscularis propria (200×); (D) pan-cytokeratin highlights the residual viable tumor cells (200×).CT scan showing bilateral hydronephrosis. (A) CT scan pre-cystectomy showing bladder thickening; (B) CT scan shows bilateral hydronephrosis; (C) Small bowel follow-through showing dilated small bowel loops, contrast ends before cecum, polypoid filling defects suggest stool in the small bowel.Metastatic high-grade urothelial carcinoma, plasmacytoid variant involving omentum and small bowel implant. (A,B) The infiltrative carcinoma consists of plasmacytoid and signet ring like cells (A:100×, B:200×); (C–F) Immunohistochemical stains demonstrate the tumor cells are positive for GATA-3 (C), CD138 (D), CK20 (E), and CK7 (F), (200×).Bladder thickening and hydronephrosis. (A) CT scan pre-cystectomy showing bilateral hydronephrosis for case 2; (B) CT scan shows bladder thickening for case 2 and calculi.Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
Topical anesthetics are one of the first line therapeutical options for men with premature ejaculation (PE). Real-life PE management often involves a range of interventions including systemic drug treatments (such as off-label and on-label selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, phosphodiesterase-5 inhibitors (PDE5Is)), topical anesthetic creams and sprays, and behavioral approaches. Among them, on-demand dapoxetine and lidocaine/prilocaine spray formulations are the only approved treatment options for lifelong PE. The earliest strategy to treat PE was based on the use of topical anesthetic agents. The rationale behind the use of anesthetics is that by reducing the glans penis sensitivity, the spinal and cerebral input of sexual arousal impulses may also be reduced. Oral SSRI proved to be effective to treat PE, but their high rate of side effects limit treatment adherence and both short and long term follow up data are lacking. Conversely, topical anesthetics have proved to increase ejaculatory latency, control, and sexual satisfaction in couple affected by PE with limited rates of adverse events. In this context, we aimed to perform a narrative review to summarize the most recent findings regarding the use of topical treatments for PE.Among sexual dysfunctions, premature ejaculation (PE) is one of the most commonly reported symptoms in everyday clinical practice. PE pathophysiology and treatment efficacy are characterized by an unfolding history of contrasting hypotheses and arguable debates [1,2,3]. In this context, the European Association of Urology (EAU) Guidelines endorses the first Evidence-Based definition of PE, developed by the International Society for Sexual Medicine (ISSM). According to such definition, PE is a sexual dysfunction characterized by; (i) ejaculation that always, or nearly always, occurs before, or within, about one minute of vaginal penetration (lifelong PE) or a clinically significant and bothersome reduction in latency time, often to about three minutes or less (acquired PE); (ii) the inability to delay ejaculation on all or nearly all vaginal penetrations; and (iii) this condition determines negative personal consequences, such as distress, bother, frustration, and/or the avoidance of sexual intimacy [1,4,5]. Over the last two decades, compelling evidence has accumulated regarding the pathophysiology of PE. As a matter of fact, positron emission tomography and functional magnetic resonance imaging studies have allowed a greater understanding of the involvement of neurotransmitters in sexual arousal and ejaculation, which contributed to improve the overall knowledge of ejaculatory disorders and orgasmic dysfunctions pathophysiology [6,7]. The increasing amount of novel evidence prompted urologists to stop considering PE as a mere psychogenic condition, and to acknowledge its possible different interconnected etiologies, i.e., organic, iatrogenic and psychogenic [6,8]. In this regard, selective serotonin reuptake inhibitors (SSRI) have been extensively investigated over the past decades and proved to be efficacious in increasing overall intravaginal ejaculation latency time (IELT) and control over ejaculation in men suffering from both, life-long and acquired PE [8,9,10]. However, patients commonly report SSRI-related side effects, which limits compliance and predisposes to treatment discontinuation in the long term [11]. In the light of these findings, topical anesthetic agents have regained popularity as a viable alternative to oral treatments [1,12]. For many years, the rationale behind the off-label prescription of topical anesthetic agents for PE was to raise the local sensitivity threshold in men who were presumed to be hypersensitive [13]. In fact, penile hypersensitivity has been considered one of the main pathologic mechanism of PE. However, the link between penile hypersensitivity and PE lacks a definitive conclusion. Xin et al. in a case-control study suggested that PE patients had hypersensitivity in the glans penis and penile shaft [13]. However, other investigations did not show a correlation between penile sensitivity and PE [14,15,16]. More recently, Guo et al. showed that patients with lifelong PE had a hypersensitivity profile in terms of peripheral sensory thresholds [17]. Penile hypersensitivity appeared to be a factor contributing to short intravaginal ejaculation latencies in lifelong PE men. Although evidence regarding penile hypersensitivity is mixed, few reports have proposed selective dorsal neurectomy as a potential treatment option for PE, due to the reduction in sensory input that are likely to attenuate central sexual arousal in men with PE [18]. Liu et al. in a group of Chinese men, showed that the dorsal penile nerve branches of patients with lifelong PE were more and thicker than those without lifelong PE, and that selective dorsal neurectomy was effective in improving IELT and ejaculatory control, with few postoperative complications [18].In this specific context, the role of topical anesthetic agents in reducing penile sensitivity in men with PE has emerged. In addition to this, more recent findings demonstrated how topical anesthetics could lead to significant benefits for both male patients and their partners in terms of increased ejaculatory latency, control, and sexual satisfaction [12,19]. This narrative review aims to discuss topical therapies for PE with a specific focus on newly released compounds.We performed a literature search for English-language original and review articles either published or e-published up until January 2021 using Google and the National Library of Medicine’s PubMed database. The mesh terms used for the search were: Premature ejaculation; topical treatment; anesthetic, cream, spray. The retrieved articles were gathered and examined. Reference lists of retrieved articles as well as relevant review articles were also studied.The exclusion criteria were as follows: (1) Editor letters and single case report; (2) non-English language publications; (3) studies with insufficient or unconfirmed information; and, (4) studies not involving PE patients. The evidence acquisition is presented according to PRISMA diagram (Figure 1).A limited number of pharmacological therapies are currently approved for PE [12]. This has led to the use of ‘off-label’ products such as local anesthetics in the everyday clinical practice [19]. When compared to PE treatments, topical agents are appealing since they are easy to use and can be applied on-demand. Moreover, local anesthetic agents do not cause systemic side effects [12,19,20]. Conversely, a downside of the application of a desensitizing substance to the glans is the potential for some degree of penile hypoesthesia. Furthermore, theoretically, the hypoesthesia might pass on to the partner, making sexual intercourse more difficult and leading to even more serious consequences such as erectile dysfunction [21]. The choice between oral therapy with SSRIs and topical anesthetics, either in cream or in spray formulation, is a decision that should be made in conjunction with the patient. Most physicians consider the use of topical therapy as a prudent first step for the treatment of PE, thanks to the favorable risk/benefit ratio of these products. Patients with PE often complain of augmented sensory responses to penile stimulation [16]. In support of this claim, the discovery of abnormal reflex pathways during ejaculation has led to the conclusion that penile hypersensitivity and PE are truly interconnected [16]. In this framework, EMLA (eutectic mixture of lidocaine-prilocaine) is an off-label anesthetic cream used for the treatment of both primary and acquired PE. In 1995, the first study on EMLA on 11 healthy men with PE showed encouraging results in delaying ejaculation [22]. Subsequently, Atikeler et al. investigated the efficacy of this preparation in a larger cohort of patients, observing a statistically significant increase in ejaculation time, which increased from around 1 min. to 6–8 min [23]. Additionally, they demonstrated that the optimal timing for EMLA application is 20 min before sexual intercourse [23]. Busato et al. demonstrated a significant increase of mean IELT among men using a lidocaine-prilocaine cream in comparison to placebo administration [24]. Similarly, Atan et al. compared the use of Sildenafil alone, Sildenafil plus EMLA and placebo confirming the superiority of topical anesthetics in delaying ejaculation as compared to placebo [25]. A recent study conducted by Gameel et al. compared the efficacy of Tramadol, Sildenafil, SSRI and a Lidocaine 2.5% anesthetic gel for the treatment of PE. Lidocaine 2.5% gel confirmed its superiority in respect to the other treatment regimens in increasing IELT (OR 5.23, p < 0.001) [26]. In conclusion, anesthetic creams have shown moderate efficacy for the treatment of primary and acquired PE. However, these preparations carry the risks of sensibility reduction for both patients and their partners, which may potentially lead to erectile dysfunction and skin irritation [27]. Additionally, cream preparations for PE are used on-demand, which could result in loss of spontaneity and subsequent loss of sexual arousal [28] causing treatment discontinuation and poor patient’s compliance.Lidocaine 9.6 % spray, marketed as ‘Studd 100’ or ‘Premjact’, has been available over-the-counter for over 25 years in some countries and it has been employed as an off-label drug to delay ejaculation. A recent study by Alghibary et al., analysed data from men with lifelong PE randomized to oral dapoxetine 60 mg or topical lidocaine 10% spray for 12 weeks and then asked to switch to the other treatment for another 12 weeks. Participants were evaluated using the Arabic Index for PE (AIPE) and the Sexual Health Inventory for Men (SHIM) questionnaire. Authors showed that both medications significantly increased both IELT and AIPE scores when compared with baseline evaluation, but the results were shown to be significantly better with topical lidocaine with respect to oral dapoxetine [28].TEMPE (topical eutectic mixture for premature ejaculation) is a proprietary formulation of lidocaine and prilocaine in a metered-dose aerosol delivery system specifically designed for use in PE. The system delivers 7.5 mg lidocaine base plus 2.5 mg prilocaine base per actuation. The mixture is alcohol-free, which limits the chance of stinging on application. Despite being oil-free, the mixture forms a clear, slightly oily, odorless solution that remains adherent to the application site and may be wiped off with a damp cloth if necessary, without the stringent need to apply a condom [29]. The metered-dose spray delivery system allows the desensitizing agents to be deposited in the form of a dose-controlled, concentrated film on the glans penis, which can then penetrate the glans within 5–10 min of its application [29]. The eutectic mixture penetrates intact keratinized skin more slowly and is therefore not likely to anesthetize the penis shaft or the hands [29]. In the first open-label pilot study, 11 patients recorded their IELT at baseline and on five subsequent encounters after the application of TEMPE 15 min before sexual intercourse [29]. The average IELT increased from 1 min 24 s to 11 min 21 s (p = 0.008), which represents an average eight-fold increase. In addition, 8 out of 11 patients and 7 out of 11 partners rated their sexual satisfaction as either ‘better’ or ‘much better’. In a more recently published phase 2, placebo-controlled trial, 54 patients using the prilocaine–lidocaine spray were able to prolong their IELT from a baseline of 1.0 min to 4.9 min [30]. The treatment was also well tolerated, with only 3 (12%) patients experiencing hypoesthesia and one patient experiencing loss of erection. None of the adverse events resulted in treatment discontinuation. The spray was also well tolerated by female partners, with only few experiencing a mild genital burning sensation during intercourse. Two double-blind placebo-controlled multi-centre phase 3 clinical trials have been completed thereafter [31,32], including over 550 PE patients assessed with the IELT and two questionnaires [index of premature ejaculation (IPE) and the premature ejaculation profile (PEP). IELT changes were mirrored in all domains of the IPE and PEP questionnaire as well as in the PEP domain scores from partners [31,33]. There was little or no evidence of systemic side effects, but only minimal desensitization of the genitalia in either patient or partner [31,33]. For decades topical anesthetic agents have been used as off-label treatments for PE, with the specific aim of raising the threshold of local sensitivity in people who were thought to be hypersensitive [16]. More recently, Fortacin™ was officially approved for use in the European Union in 2013 and finally launched in the United Kingdom in November 2016 for the treatment of men with primary PE [34]. Fortacin is a metered-dose aerosol spray and contains purely base (uncharged) forms of the local anesthetics lidocaine 150 mg/mL and prilocaine 50 mg/mL, with no excipients, except the spray propellant (norflurane) [34]. An original prescription information leaflet suggests using the compound as follows: One dose, namely three sprays, to be applied on the glans penis at least five minutes before sexual attempts [34]. Prost et al. found that Fortacin™ increased ejaculatory latency, control, and sexual satisfaction in men with primary PE, demonstrating the significant benefits for both patients and their partners when using the drug [20]. Likewise, other groups confirmed the above mentioned findings making local anesthetics a viable alternative for lifelong and acquired PE [13,15,29]. Recently, the results from an expert panel discussion on the management of PE reported that most patients perceive PE as a bother rather than a disease, and that on-demand treatment options and the topical route of administration are mostly preferred [35].This formulation has been reported to optimize the penetration through the glans surface leading to a rapid reduction in penile sensitivity (within 5 min)—namely termed desensitization—without adversely affecting the actual sensation of ejaculation. Moreover, Fortacin™ administration might be “personalized” in clinical practice in order to obtain a further patient-oriented treatment. Only few reports have investigated the efficacy and tolerability of a combination therapy of SSRI and topical anesthetics. Metin et al. [36] investigated the effect of on-demand fluoxetine 20 mg taken about 4 h before sexual intercourse, followed by 3 months of combination therapy of fluoxetine plus lidocaine ointment (applied 30 min prior to sexual activity) in 46 men with PE. Authors reported that PE grade and IELT improved with combination treatment and that 86.9% of patients reported a total significant and moderate improvement in PE rate. In another small trial fluoxetine 20 mg/day followed by fluoxetine 40 mg/day was compared to the outcome of a combination therapy of fluoxetine 20 mg/day plus local lidocaine for 2 months [25]. Patients under combination therapy showed higher rates of PE improvement compared to those in monotherapy. Only a limited number of studies investigated the efficacy of combination therapy of local anesthetics and phosphodiesterase type 5 inhibitors (PDE5i) for PE. Atan et al. assessed the effect of combination therapy with sildenafil and EMLA-cream vs. monotherapy and placebo in 84 men with PE. They found that combination treatment had a higher efficacy (86.4%) compared to placebo (40%) and to either monotherapy (sildenafil 50 mg: 55%; EMLA: 77.3%) [20]. In another study, including 78 men with primary PE, the efficacy of lidocaine spray 10 g/100 mL, tadalafil 5 mg daily and tadalafil 5 mg daily plus lidocaine spray was investigated over 3 months [37]. Mean IELT and satisfaction scores were significantly higher in patients with combination therapy than those of patients on monotherapy at 3 months.Despite being one of the most commonly reported sexual dysfunctions, which treatment is adequate and efficacious for PE remains controversial [38,39]. SSRI represented the cornerstone for PE treatment over the last few decades and dapoxetin, a short-acting SSRI, has been the only officially approved oral drug for PE in Europe and many countries worldwide. Nevertheless, SSRI treatment is associated with high rates of treatment discontinuation at both short and long-term follow up [9,12,40]. Commonly reported reasons for discontinuation are efficacy below expectations, costs, side effects and loss of interest in sexual activity [40]. In light of this issues, topical anesthetic agents have regained importance as possible alternatives to oral treatments.When compared to systemic therapy, topical anesthetic compounds offer various advantages such as lack of systemic side effects and limited number of local reactions. However, depending on the formulation, they may require a latency time between application and maximum effect. Furthermore, they should either to be used with a condom, washed-off or wiped-off before intercourse, which could have an effect on spontaneity during sex (Table 1). Local anesthetic cream formulations (lidocaine-prilocaine and dyclonine-alprostadil) require application 5–20 min beforehand and the potential use of a condom, whereas spray formulations (lidocaine–prilocaine, TEMPE) have to be applied 5–15 min in advance [21]. The new dose-metered lidocaine-prilocaine spray (Fortacin) has gained increasing popularity among PE-affected couples, especially because of its unique galenic preparation, which renders its handling effortless and customer friendly. In addition to this, several studies have proved the clinical efficacy of lidocaine-prilocaine spray in terms of IELT improvement, ejaculatory control, sexual satisfaction, and distress [19]. Physicians should always bear in mind that the pathophysiology of PE is multifactorial, with an interlink between psychogenic, organic and neurobiological factors. Consequently, it is likely that the most efficacious treatment of PE is multifactorial as well.Topical anesthetics proved to be safe and effective as a treatment option for men with PE of various types. Patients treatment compliance is higher than that for oral medications. The new dose-metered lidocaine-prilocaine spray has shown promising results for the treatment of lifelong PE in terms of efficacy, and because of its unique galenic preparation, its handling is easy and patient friendly. Combination therapy of local anesthetics and oral medications seems to be superior than monotherapy alone, but data is still scarce to support its systematic use.Conceptualization, L.B., F.B., A.S. and E.P.; methodology, E.P.; writing—original draft preparation, E.P., F.B., L.B.; writing—review and editing, L.B., C.B. and A.S.; All authors have read and agreed to the published version of the manuscript.This research received no external funding.The authors declare no conflict of interest.Evidence acquisition according to PRISMA diagram.Summary of advantages/disadvantages of topical treatment for PE.Significant increase in ejaculation time compared to placeboAdditive effect when used in combination therapyRisk for sensibility reduction for both partners and skin irritation with subsequent loss of sexual desire and erectile dysfunctionCondom use is advised with cream formulationsIncrease ejaculatory latency, control, and sexual satisfaction in men with primary PEMetered-dose aerosol delivery system allows for dose-controlled actionNot likely to anesthetize the penis shaft or the handsCondom use is not necessaryMild hypoesthesia and genital burningRare cases of erectile dysfunctionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
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