Diagnostic approach in TFE3-rearranged renal cell carcinoma: a multi-institutional international survey

2021 ◽  
pp. jclinpath-2020-207372
Author(s):  
Mahmut Akgul ◽  
Sean R Williamson ◽  
Dilek Ertoy ◽  
Pedram Argani ◽  
Sounak Gupta ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Online Survey ◽  
In Situ Hybridisation ◽  
Cathepsin K ◽  
Diagnostic Approach ◽  
Background Staining ◽  
Abundant Cytoplasm ◽  
Diagnostic Work

Transcription factor E3-rearranged renal cell carcinoma (TFE3-RCC) has heterogenous morphologic and immunohistochemical (IHC) features.131 pathologists with genitourinary expertise were invited in an online survey containing 23 questions assessing their experience on TFE3-RCC diagnostic work-up.Fifty (38%) participants completed the survey. 46 of 50 participants reported multiple patterns, most commonly papillary pattern (almost always 9/46, 19.5%; frequently 29/46, 63%). Large epithelioid cells with abundant cytoplasm were the most encountered cytologic feature, with either clear (almost always 10/50, 20%; frequently 34/50, 68%) or eosinophilic (almost always 4/49, 8%; frequently 28/49, 57%) cytology. Strong (3+) or diffuse (>75% of tumour cells) nuclear TFE3 IHC expression was considered diagnostic by 13/46 (28%) and 12/47 (26%) participants, respectively. Main TFE3 IHC issues were the low specificity (16/42, 38%), unreliable staining performance (15/42, 36%) and background staining (12/42, 29%). Most preferred IHC assays other than TFE3, cathepsin K and pancytokeratin were melan A (44/50, 88%), HMB45 (43/50, 86%), carbonic anhydrase IX (41/50, 82%) and CK7 (32/50, 64%). Cut-off for positive TFE3 fluorescent in situ hybridisation (FISH) was preferably 10% (9/50, 18%), although significant variation in cut-off values was present. 23/48 (48%) participants required TFE3 FISH testing to confirm TFE3-RCC regardless of the histomorphologic and IHC assessment. 28/50 (56%) participants would request additional molecular studies other than FISH assay in selected cases, whereas 3/50 participants use additional molecular cases in all cases when TFE3-RCC is in the differential.Optimal diagnostic approach on TFE3-RCC is impacted by IHC and/or FISH assay preferences as well as their conflicting interpretation methods.

scholarly journals Cathepsin K: A Novel Diagnostic and Predictive Biomarker for Renal Tumors

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2441
Author(s):  
Anna Caliò ◽  
Matteo Brunelli ◽  
Stefano Gobbo ◽  
Pedram Argani ◽  
Enrico Munari ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Therapy Response ◽  
Cathepsin K ◽  
Mtor Inhibitors ◽  
Predictive Marker ◽  
Predictive Biomarker ◽  
Renal Tumors ◽  
Epithelioid Angiomyolipoma

Cathepsin K is a papain-like cysteine protease with high matrix-degrading activity. Among several cathepsins, cathepsin K is the most potent mammalian collagenase, mainly expressed by osteoclasts. This review summarizes most of the recent findings of cathepsin K expression, highlighting its role in renal tumors for diagnostic purposes and as a potential molecular target. Indeed, cathepsin K is a recognized diagnostic tool for the identification of TFE3/TFEB-rearranged renal cell carcinoma, TFEB-amplified renal cell carcinoma, and pure epithelioid PEComa/epithelioid angiomyolipoma. More recently, its expression has been observed in a subgroup of eosinophilic renal neoplasms molecularly characterized by TSC/mTOR gene mutations. Interestingly, both TSC mutations or TFE3 rearrangement have been reported in pure epithelioid PEComa/epithelioid angiomyolipoma. Therefore, cathepsin K seems to be a downstream marker of TFE3/TFEB rearrangement, TFEB amplification, and mTOR pathway activation. Given the established role of mTOR inhibitors as a pharmacological option in renal cancers, cathepsin K could be of use as a predictive marker of therapy response and as a potential target. In the future, uropathologists may implement the use of cathepsin K to establish a diagnosis among renal tumors with clear cells, papillary architecture, and oncocytic features.

scholarly journals MiT Family Translocation Renal Cell Carcinoma: from the Early Descriptions to the Current Knowledge

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1110 ◽  
Author(s):  
Anna Caliò ◽  
Diego Segala ◽  
Enrico Munari ◽  
Matteo Brunelli ◽  
Guido Martignoni
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clinical Course ◽  
Current Knowledge ◽  
Wide Spectrum ◽  
Cathepsin K ◽  
World Health ◽  
Epithelioid Angiomyolipoma ◽  
Immunohistochemical Markers

The new category of MiT family translocation renal cell carcinoma has been included into the World Health Organization (WHO) classification in 2016. The MiT family translocation renal cell carcinoma comprises Xp11 translocation renal cell carcinoma harboring TFE3 gene fusions and t(6;11) renal cell carcinoma harboring TFEB gene fusion. At the beginning, they were recognized in childhood; nevertheless, it has been demonstrated that these neoplasms can occur in adults as well. In the nineties, among Xp11 renal cell carcinoma, ASPL, PRCC, and SFPQ (PSF) were the first genes recognized as partners in TFE3 rearrangement. Recently, many other genes have been identified, and a wide spectrum of morphologies has been described. For this reason, the diagnosis may be challenging based on the histology, and the differential diagnosis includes the most common renal cell neoplasms and pure epithelioid PEComa/epithelioid angiomyolipoma of the kidney. During the last decades, many efforts have been made to identify immunohistochemical markers to reach the right diagnosis. To date, staining for PAX8, cathepsin K, and melanogenesis markers are the most useful identifiers. However, the diagnosis requires the demonstration of the chromosomal rearrangement, and fluorescent in situ hybridization (FISH) is considered the gold standard. The outcome of Xp11 translocation renal cell carcinoma is highly variable, with some patients surviving decades with indolent disease and others dying rapidly of progressive disease. Despite most instances of t(6;11) renal cell carcinoma having an indolent clinical course, a few published cases demonstrate aggressive behavior. Recently, renal cell carcinomas with TFEB amplification have been described in connection with t(6;11) renal cell carcinoma. Those tumors appear to be associated with a more aggressive clinical course. For the aggressive cases of MiT family translocation carcinoma, the optimal therapy remains to be determined; however, new target therapies seem to be promising, and the search for predictive markers is mandatory.

scholarly journals Comprehensive Immunoprofiles of Renal Cell Carcinoma Subtypes

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 602 ◽  
Author(s):  
Moonsik Kim ◽  
Jin Woo Joo ◽  
Seok Joo Lee ◽  
Yoon Ah Cho ◽  
Cheol Keun Park ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Collecting Duct ◽  
Cathepsin K ◽  
Renal Tumors ◽  
Duct Carcinoma ◽  
Epithelial Tumors ◽  
Papillary Type

In recent years, renal epithelial tumors have been among the fastest reclassifying tumors, requiring updates to the tumor classification system. Nonetheless, immunohistochemistry (IHC) remains the most widely used tool for renal epithelial tumors. In this proposal, we aimed to create the most efficient IHC panel for categorizing the diverse subtypes of renal tumors, and to find out more specific immunohistochemical results in each subtype or each antibody. A total of 214 renal tumors were analyzed using 10 possible IHC markers to differentiate subtypes, including three major renal cell carcinoma (RCC) subtypes, clear-cell type (50 cases), papillary type (50 cases), and chromophobe type (20 cases), and minor subtypes (MiT RCC, 13 cases; collecting duct carcinoma, 5 cases; and oncocytoma, 10 cases). A triple immunomarker (cytokeratin 7 (CK7)-carbonic anhydrase IX (CAIX)- alpha-methylacyl-CoA racemase (AMACR)) panel is useful in particular high-grade clear-cell tumors. If IHC remains ambiguous, the use of an adjunctive panel can be suggested, including CD10, epithelial membrane antigen, cathepsin K, c-kit, hepatocyte nuclear factor 1-β, and E-cadherin. For an efficient immunohistochemical strategy for subtyping of RCC, we conclude that the CK7-CAIX-AMACR panel is the best primary choice for screening subtyping.

Cytogenetic changes in renal cell carcinoma: Basis for sensitivity and resistance to everolimus.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 403-403
Author(s):  
Imogen Rose Caldwell ◽  
Paul Oei ◽  
Daniel Ng ◽  
Peter C.C. Fong ◽  
Reuben James Broom
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
In Situ Hybridisation ◽  
Predictive Biomarkers ◽  
Mtor Inhibitors ◽  
Fluorescence In Situ Hybridisation ◽  
Translational Study ◽  
Cytogenetic Changes ◽  
Tissue Specimens

403 Background: The mTOR inhibitors have improved outcomes for pts with metastatic renal cell carcinoma (mRCC) but the duration of benefit is variable. Currently there are no predictive biomarkers for pre-selecting pts who are likely to respond to these agents. We undertook an exploratory translational study evaluating cytogenetic changes in the context of response to everolimus therapy. Methods: 10 pts with mRCC treated with everolimus therapy were enrolled. Pre-treatment paraffin-embedded tissue specimens were analysed for cytogenetic changes using fluorescence in situ hybridisation (FISH) and clinical data including PFS (RECIST 1.1) were obtained. The gene probes chosen for this analysis were; VHL, FHIT, FGFR1/3, PDGFb, PDGFRb, EGFR, MYC and IGH@. Results: Results are displayed in the table below. The median PFS was 8.25mo (months). Eight pts were treated 1st-line (on clinical trial), one 2nd-line and one 3rd-line. The longest responder (PFS 25.5mo, 3rd-line) had a normal VHL status but loss of FHIT. Two pts with the longest PFS and one with a PFS of 5.5mo had gain of both PDGFb and PDGFRb. Gain of FGFR1 and FGFR3 was seen in two and three pts respectively. Two specimens were unsuitable for full analysis. Conclusions: Loss of FHIT but a normal VHL status was seen in one pt with mRCC who had an enduring response to everolimus. Concomitant gain of PDGFband PDGFRb was observed in three pts with a good response. FGFR1/3 may be of relevance in the setting of alternative targeted therapies. Further research evaluating the utility of these potential biomarkers is required. [Table: see text]

Frustration and distress during treatment for advanced renal cell carcinoma.

2018 ◽  
Vol 36 (34_suppl) ◽  
pp. 47-47
Author(s):  
Cristiane Decat Bergerot ◽  
Dena Battle ◽  
Paulo Gustavo Bergerot ◽  
Daniel J. George ◽  
Hans J. Hammers ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Online Survey ◽  
Clear Cell ◽  
Psychosocial Support ◽  
Qualitative Content Analysis ◽  
Advanced Renal Cell Carcinoma ◽  
Cross Sectional ◽  
Common Diagnosis

47 Background: Treatment strategies for advanced renal cell carcinoma (aRCC) have improved over the past 15 years. Durable responses are now achievable, giving rise to the possibility of cure in a small proportion of this population. However, it is not clear how patients are coping with more protracted courses of treatment. We sought to determine sources of frustration among patients diagnosed with aRCC. Methods: We performed a cross-sectional analysis of data derived from an online survey distributed via social media from April to June, 2017. We assessed source of frustration using an open-ended question: “In your own words, what has frustrated you most about your medical care related to your diagnosis?”. We assessed distress using the Distress Thermometer. Qualitative content analysis was performed to characterize responses related to frustration. Descriptive statistics was generated and the Kruskal-Wallis test was used to explore the relationship between clinical characteristics and sources of frustration. Results: We enrolled 217 patients with aRCC. The majority were male (52.3%), and white (93.5%). Clear cell histology (84.2%) was the most common diagnosis. Patients reported high levels of distress (M = 6.4; SD = 2.8). Sources of frustration were documented in 71.9% of patients, and were most commonly related to distrust of the cancer care system (12.4%), fear of progression (11.5%), lack of information (11.1%), financial concerns (9.7%), communication between patient and physician (7.8%), treatment side effects (4.6%), lack of available research (4.1%), mistrust of physician’s knowledge (4.1%), and access to supportive care (2.8%). Higher levels of frustration were associated with higher levels of distress (P = 0.01). Patients with non-clear cell RCC more commonly reported an emotional source of frustration (P = 0.02). Conclusions: Patients with aRCC report high levels of distress and frustration with their diagnosis and treatment. The most frequent drivers of frustration can suggest opportunities to maximize support to patients and their families. A better understanding of their disease and prognosis, addressing financial concerns and offering psychosocial support may alleviate frustration amongst patients with aRCC.

Diagnostic Approach to Hereditary Renal Cell Carcinoma

2015 ◽  
Vol 204 (5) ◽  
pp. 1031-1041 ◽  
Author(s):  
Shiva Gupta ◽  
Hyunseon C. Kang ◽  
Dhakshina Moorthy Ganeshan ◽  
Tharakeswara Kumar Bathala ◽  
Vikas Kundra
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Diagnostic Approach

Cytogenetic changes in metastatic renal cell carcinoma: Basis for sensitivity and resistance to everolimus.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15050-e15050
Author(s):  
Imogen Rose Caldwell ◽  
Paul Oei ◽  
Daniel Ng ◽  
Beth Caudwell ◽  
Peter C.C. Fong ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
In Situ Hybridisation ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Mtor Inhibitors ◽  
Fluorescence In Situ Hybridisation ◽  
Cytogenetic Changes

e15050 Background: The mTOR inhibitors have improved outcomes for pts with metastatic renal cell carcinoma (mRCC) but the duration of benefit is variable. Currently there are no predictive biomarkers for pre-selecting pts who are likely to benefit from these agents. We undertook an exploratory translational study evaluating cytogenetic changes in the context of benefit from everolimus therapy. Methods: 10 pts with clear cell mRCC treated with everolimus therapy were enrolled. 2 pts had both primary & metastatic specimens. Pre-treatment paraffin-embedded tissue specimens were analysed for cytogenetic changes using fluorescence in situ hybridisation (FISH) & clinical data including Progression-free Survival (PFS) (RECIST 1.1) were obtained. The gene probes chosen for this analysis were: VHL, FHIT, PDGFβ, PDGFRβ, FGFR1, FGFR3, EGFR, MYC, PTEN & IGH@. Results: Results are displayed in the table. The median PFS was 7.5 months (mo), including 4 pts who remain on treatment. 8 pts were treated 1st-line, one 2nd-line & one 3rd-line. The longest responder (PFS 28 mo, 3rd-line) had a normal VHL status but loss of FHIT. 2 pts with the longest PFS had gain of both PDGFβ & PDGFRβ. Changes were observed between the primary & metastatic specimens including the acquisition of gain of PDGFβ & MYC (these pts remain progression-free on treatment). Conclusions: Loss of FHIT but a normal VHL status was seen in one pt with mRCC who had an enduring response to everolimus. Concomitant gain of PDGFβ & PDGFRβ was observed in 5 pts including 2 with prolonged benefit. Acquisition of gains in gene status suggests evolution of genetic changes between primary & metastatic specimens. [Table: see text]

Patient-reported outcomes on treatment-related side effects in renal cell carcinoma.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 654-654
Author(s):  
Dena Battle ◽  
Wendy Kimryn Rathmell ◽  
Eric Jonasch ◽  
Pavlos Msaouel ◽  
Adam P. Stern ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Native American ◽  
Side Effects ◽  
Cell Carcinoma ◽  
Dose Reduction ◽  
Side Effect ◽  
Renal Cell ◽  
Online Survey ◽  
Medical Oncologist ◽  
Patient Reported

654 Background: Effective management of treatment related toxicities is crucial to maximizing patient outcomes and enhancing quality of life in renal cell carcinoma. Little is known about patient perception and reporting of side effects in a real world setting outside clinical trials. We sought to gather independent data from online patient communities to estimate gaps in communication and reporting. Methods: KCCure conducted an anonymous online survey from 07/19 to 09/19 using questions related to side-effect experience and management. Results: 1,136 patients (median age 57 years [range 28-86], 54% male) participated, 411 patients on systemic therapy were asked about side-effects. 47% of patients reported bothersome side effects impacting their daily lives. The most poorly managed side-effect was fatigue (25%), followed by taste alteration (15%) and loss of appetite (15%). Only 50% of patients are confident their medical oncologist will offer help for side effects, and 20% are worried that reporting side effects may result in dose reduction or treatment discontinuation. 6% of patients don’t talk about their side effects. Patients who identified as non-white (Hispanic, African American, Asian/Pacific Islander and Native American) were three times less likely to talk about side effects. 51% indicated the best advice on managing treatment related side effects was provided by their medical oncologist; 40% seek advice from online patient communities and 35% from advocacy organizations. Only 8% used manufacturer support websites. 13% had never had any concomitant medication prescribed to manage side effects. Major unreported side effects are sexual dysfunction, cognitive impairment and vision disturbances. Conclusions: The majority of patients experience treatment related side-effects on a regular basis, but underreporting may be significant due to a variety of factors, including fear of dose-reduction or discontinuation. Sexual side-effects are underreported. Future studies need to explore differences in reporting for minority populations as well as side effect experiences according to the class of agent prescribed, and the setting in which treatment occurs.

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