The 5th edition WHO Classification of Urinary and Male Genital Tumours (2022) introduces significant changes relevant to daily practice, especially in the completely restructured renal cell tumor ...chapters. Herein we highlight the most important diagnostic updates of known kidney tumor types, new and molecularly defined entities and emerging/provisional entities.
Eosinophilic solid and cystic renal cell carcinoma (ESC-RCC) is a novel entity of rare tumors with rather unique morphology and immunohistochemical profile. Until recently these tumors were ...characterized by indolent behavior. Herein, we describe a series of six primary and metastatic ESC-RCCs morphologically and immunophenotypically mimicking epithelioid angiomyolipoma (eAML). Retrospective review of unclassified RCCs with oncocytic phenotype yielded several candidate cases, 4 of which fulfilled diagnostic criteria after additional work-up. Three female patients and one male (median age 46) presented with unifocal tumors ranging from 1.5 cm to 20.5 cm (median 5 cm). On follow-up (median 32 months), 2 younger patients had no signs of tumor recurrence, but older patients presented with advanced disease. A 50 year-old female developed numerous bone metastases and tumor progression despite aggressive treatment. Two of these metastases were analyzed showing morphology and immunoprofile similar to the primary tumor. 50 year-old male had locally aggressive tumor invading adrenal gland and retroperitoneum. All cases exhibited ESC-like architecture of solid sheets, tight nests and variably sized cysts with hobnailed lining, as well as foci of diffuse growth with poorly cohesive brightly eosinophilic cells. Characteristic cytoplasmic stippling and coarse granularity was present in all cases including compact cytoplasmic “Leishmaniasis-like” globules. Due to high suspicion of eAML, immunostaining panels included melanocytic markers, cytokeratins and RCC-specific markers. All ESC-RCC were positive for CK20 and melanocytic markers Melan-A, Cathepsin-K or HMB45, as well as PAX8, whereas EMA, pan-cytokeratin, CK7, CKIT, CD10, CAIX were negative. Comparison with 5 eAML cases including 2 malignant tumors showed similar morphology and immune reactivity except for more frequent expression of HMB45 and lack of PAX8 positivity. In conclusion, we report 2 cases of aggressive ESC-RCC course including widespread bone metastases in addition to 2 typical indolent tumors. ESC-RCC and eAML could present with overlapping morphology and immunophenotype causing diagnostic difficulty and expanding our understanding of these rare tumors.
•Eosinophilic solid and cystic renal cell carcinoma (ESC-RCC) have malignant potential in ~5% cases.•First report of ESC-RCC cases with locally invasive disease and extensive bone metastases.•ESC-RCC mimics epithelioid angiomyolipoma morphologically and immunophenotypically.
Translocation renal cell carcinoma (tRCC) with TFE3 gene rearrangements has been born as a distinct entity 20 years ago. These relatively rare tumors were notable among other RCC subtypes because of ...their disproportionally high incidence among children and young adults. Initial reports were focused on describing unifying morphologic criteria and typical clinical presentation. Follow-up studies of ancillary immunohistochemical and hybridization techniques provided additional diagnostic tools allowing recognition of tRCC tumors in practice. However, a growing body of literature also expanded the clinicomorphologic spectrum of tRCCs, to include a significant morphologic overlap with other RCC variants thus blurring the diagnostic clarity of this entity. More recent molecular studies utilizing next-generation sequencing technology accelerated recognition of numerous novel gene partners fusing at different breakpoints with the TFE3 gene. Accumulating data indicates that morphologic and clinical heterogeneity of tRCC could be explained by fusion subtypes, and knowledge of TFE3 partnering genes may be important in predicting tumor behavior. Herein we provided a comprehensive analysis of ∼400 tRCC cases with known TFE3 fusion partners, estimated their relative incidence and summarized clinicomorphologic features associated with most common fusion subtypes. Our data was based on an extensive literature review and had a special focus on comparing immunohistochemistry, fluorescent in situ hybridization and contemporary molecular studies for the accurate diagnosis of tRCC.
Over the past 20 years, the number of subtypes of renal epithelial cell neoplasia has grown. This growth has resulted from detailed histological and immunohistochemical characterization of these ...tumors and their correlation with clinical outcomes. Distinctive molecular phenotypes have validated the unique nature of many of these tumors. This growth of unique renal neoplasms has continued after the 2016 World Health Organization (WHO) Classification of Tumours. A consequence is that both the pathologists who diagnose the tumors and the clinicians who care for these patients are confronted with a bewildering array of renal cell carcinoma variants. Many of these variants have important clinical features, i.e. familial or syndromic associations, genomics alterations that can be targeted with systemic therapy, and benignancy of tumors previously classified as carcinomas. Our goal in the review is to provide a practical guide to help recognize these variants, based on small and distinct sets of histological features and limited numbers of immunohistochemical stains, supplemented, as necessary, with molecular features.
Renal cell tumors with oncocytic phenotypes represent a daily challenge, with several novel, emerging, and provisional entities enriching the diagnostic repertoire. Eosinophilic solid and cystic ...renal cell carcinoma (ESC-RCC), low-grade oncocytic tumor (LOT), and eosinophilic vacuolated tumor (EVT) have been recognized as unique entities, although their distinctive nature remains controversial. Although most of these tumors are sporadic, rare reports of similar tumors in tuberous sclerosis complex (TSC) have been published. We describe multifocal, often bilateral, tumors in six patients without personal or family history of syndromic diseases. More than 60 tumors in various combinations were identified in 10 nephrectomies and one biopsy encompassing ESC-RCC (n = 6), LOT (n = 14), EVT (n = 1), clear cell RCC with fibromyomatous stroma (n = 12), clear cell RCC (n = 2), angiomyolipomas (AMLs; n > 20), unclassified renal cell tumors (n = 2), papillary adenomas (n = 4), and renomedullary interstitial cell tumor (n = 1). TSC1 germline pathogenic mutations were confirmed in two patients. A tumor without germline testing in a third patient revealed TSC1 biallelic inactivation. Two additional patients had molecular testing, which excluded common renal mutations and syndromes. We provide the first evidence of co-existence in the same organ and unequivocal relatedness of ESC-RCC, EVT, and LOT. End-stage renal disease was present in three of six patients with precursor lesions to all above tumors within adjacent renal parenchyma. In conclusion, identification of multifocal tumors with TSC-like morphology, especially in association with AMLs, could be the first manifestation of clinically silent TSC guiding clinical recommendations for further genetic testing and/or treatment recommendations.
•Multifocal bilateral oncocytic tumors should prompt testing for tuberous sclerosis complex even without other clinical signs.•First report of simultaneous ESC-RCC, EVT, and LOT in the same kidney as direct evidence of their relatedness.•Novel descriptions of ESC-RCC, LOT, and RCC-FMS precursor lesions and their association with end-stage renal disease.
The significance of ERG in human prostate cancer is unclear because mouse prostate is resistant to ERG-mediated transformation. We determined that ERG activates the transcriptional program regulated ...by YAP1 of the Hippo signaling pathway and found that prostate-specific activation of either ERG or YAP1 in mice induces similar transcriptional changes and results in age-related prostate tumors. ERG binds to chromatin regions occupied by TEAD/YAP1 and transactivates Hippo target genes. In addition, in human luminal-type prostate cancer cells, ERG binds to the promoter of YAP1 and is necessary for YAP1 expression. These results provide direct genetic evidence of a causal role for ERG in prostate cancer and reveal a connection between ERG and the Hippo signaling pathway.
•Upregulation of ERG is sufficient to cause age-dependent prostate tumors in mice•ERG transcriptional output is similar to the output of YAP1 of the Hippo pathway•ERG is necessary for YAP1 expression in luminal-type human prostate cancer cells•Activation of YAP1 is sufficient to cause age-dependent prostate tumors in mice
Nguyen et al. show that ERG activates YAP1-regulated transcriptional output and that activation of ERG or YAP1 in mouse prostate induces similar transcriptional changes and age-related prostate tumors. Moreover, pharmacological inhibition of YAP1 suppresses growth of ERG-positive human prostate tumor xenografts.
Therapy with anti-PD-L1 immune check-point inhibitors is approved for several cancers, including advanced urothelial carcinomas. PD-L1 prevalence estimates vary widely in bladder cancer, and lack of ...correlation between expression and clinical outcomes and immunotherapy response may be attributed to methodological differences of the immunohistochemical reagents and procedures. We characterized PD-L1 expression in 235 urothelial carcinomas including 79 matched pairs of primary and metastatic cancers using a panel of four PD-L1 immunoassays in comparison with RNAscope assay using PD-L1-specific probe (CD274). The antibody panel included three FDA-approved clones (22C3 for pembrolizumab, 28.8 for nivolumab, SP142 for atezolizumab), and a commonly used clone E1L3N. Manual scoring of tissue microarrays was performed in each of 235 tumors (624 tissue cores) and compared to an automated image analysis. Expression of PD-L1 in tumor cells by ≥1 marker was detected in 41/142 (28.9%) primary tumors, 13/77 (16.9%) lymph nodes, and 2/16 (12.5%) distant metastases. In positive cases, high PD-L1 expression (>50% cells) was detected in 34.1% primary and 46.7% metastases. Concordant PD-L1 expression status was present in 71/79 (89.9%) cases of matched primary and metastatic urothelial carcinomas. PD-L1 sensitivity ranked from highest to lowest as follows: RNAscope, clone 28.8, 22C3, E1L3N, and SP142. Pairwise concordance correlation coefficients between the four antibodies in 624 tissue cores ranged from 0.76 to 0.9 for tumor cells and from 0.30 to 0.85 for immune cells. RNA and protein expression levels showed moderate to high agreement (0.72-0.87). Intra-tumor expression heterogeneity was low for both protein and RNA assays (interclass correlation coefficients: 0.86-0.94). Manual scores were highly concordant with automated Aperio scores (0.94-0.97). A significant subset of 56/235 (23.8%) urothelial carcinomas stained positive for PD-L1 with high concordance between all four antibodies and RNA ISH assay. Despite some heterogeneity in staining, the overall results are highly concordant suggesting diagnostic equivalence of tested assays.
Prostate cancer is dependent on androgen receptor (AR) activation. Optimal AR antagonism may effectively cytoreduce local disease and suppress or eliminate micrometastases. We evaluated neoadjuvant ...therapy prior to prostatectomy with the potent AR antagonist enzalutamide (enza) either alone or in combination with dutasteride (dut) and leuprolide (enza/dut/luteinizing hormone-releasing hormone analogues LHRHa).
Forty-eight of 52 men with intermediate or high-risk localized prostate cancer proceeded to prostatectomy after neoadjuvant enzalutamide or enza/dut/LHRHa for 6 months. We assessed pathologic complete response (pCR), minimal residual disease (MRD; ≤3 mm maximum diameter of residual disease), residual cancer burden (RCB), and expression of PSA and serum and tissue androgen concentrations. We compared the proportion of patients with pCR in each treatment arm with a historical control rate of 5%, based on previous reports of flutamide with LHRHa.
In the enzalutamide arm, none of the 25 patients achieved pCR or MRD. In the enza/dut/LHRHa arm, one of 23 patients (4.3%) achieved pCR and 3 of 23 (13.0%) achieved MRD. Median RCB was higher in the enzalutamide arm than in the enza/dut/LHRHa arm (0.41 cm
vs. 0.06 cm
, respectively). Tissue testosterone and dihydrotestosterone levels correlated with RCB. No adverse events leading to study drug discontinuation were reported.
Combination therapy with enza/dut/LHRHa resulted in pCR and MRD rates comparable with historical controls. Evidence of continued AR activity in residual tumor suggests that AR signaling may contribute to survival. Strategies to more effectively ablate AR activity are warranted to determine whether more substantial antitumor effects are observed.
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The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in renal neoplasia, particularly focusing on the newly accumulated evidence post-2016 World Health ...Organization (WHO) classification. In the era of evolving histo-molecular classification of renal neoplasia, morphology is still key. However, entities (or groups of entities) are increasingly characterized by specific molecular features, often associated either with recognizable, specific morphologies or constellations of morphologies and corresponding immunohistochemical profiles. The correct diagnosis has clinical implications leading to better prognosis, potential clinical management with targeted therapies, may identify hereditary or syndromic associations, which may necessitate appropriate genetic testing. We hope that this undertaking will further facilitate the identification of these entities in practice. We also hope that this update will bring more clarity regarding the evolving classification of renal neoplasia and will further reduce the category of “unclassifiable renal carcinomas/tumors”. We propose three categories of novel entities: (1) “Novel entity”, validated by multiple independent studies; (2) “Emerging entity”, good compelling data available from at least two or more independent studies, but additional validation is needed; and (3) “Provisional entity”, limited data available from one or two studies, with more work required to validate them. For some entities initially described using different names, we propose new terminologies, to facilitate their recognition and to avoid further diagnostic dilemmas. Following these criteria, we propose as novel entities: eosinophilic solid and cystic renal cell carcinoma (ESC RCC), renal cell carcinoma with fibromyomatous stroma (RCC FMS) (formerly RCC with leiomyomatous or smooth muscle stroma), and anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC). Emerging entities include: eosinophilic vacuolated tumor (EVT) and thyroid-like follicular renal cell carcinoma (TLFRCC). Finally, as provisional entities, we propose low-grade oncocytic tumor (LOT), atrophic kidney-like lesion (AKLL), and biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC).
Microarray profiling of invasive breast carcinomas has identified five distinct subtypes of tumors (luminal A, luminal B, normal breast-like, HER2 overexpressing, and basal-like) that are associated ...with different clinical outcomes. The basal-like subtype is associated with poor clinical outcomes and is the subtype observed in BRCA1-related breast cancers. The aim of this study was to characterize the histologic and immunophenotypic properties of breast basal-like carcinomas that were first positively identified using DNA microarray analysis. Detailed histologic review was performed on 56 tumors with known microarray profiles (23 basal-like, 23 luminal, and 12 HER2+). Immunohistochemistry for estrogen receptor (ER), HER2, EGFR, smooth muscle actin (SMA), p63, CD10, cytokeratin 5/6, cytokeratin 8/18, and vimentin was performed on 18 basal-like, 16 luminal, and 12 HER2+ tumors. The basal-like tumors were grade 3 ductal/NOS (21/23) or metaplastic (2/23) carcinomas that frequently showed geographic necrosis (17/23), a pushing border of invasion (14/23), and a stromal lymphocytic response (13/23). Most basal-like tumors showed immunoreactivity for vimentin (17/18), luminal cytokeratin 8/18 (15/18), EGFR (13/18), and cytokeratin 5/6 (11/18), while positivity for the myoepithelial markers SMA (4/18), p63 (4/18) and CD10 (2/18) was infrequent. All basal-like tumors tested were ER− and HER2−. Morphologic features significantly associated with the basal-like subtype included markedly elevated mitotic count (P<0.0001), geographic tumor necrosis (P=0.0003), pushing margin of invasion (P=0.0001), and stromal lymphocytic response (P=0.01). The most consistent immunophenotype seen in the basal-like tumors was negativity for ER and HER2, and positivity for vimentin, EGFR, cytokeratin 8/18, and cytokeratin 5/6. The infrequent expression of myoepithelial markers in basal-like carcinomas does not support a direct myoepithelial cell derivation of these tumors. These findings should further assist in the identification of basal-like carcinomas in clinical specimens, facilitating treatment and epidemiologic studies of this tumor subtype.
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