Xp11 Translocation Research Articles

A genetic basis for sex differences in Xp11 translocation renal cell carcinoma

Xp11 translocation renal cell carcinoma (tRCC) is a rare, female-predominant cancer driven by a fusion between the transcription factor binding to IGHM enhancer 3 (TFE3) gene on chromosome Xp11.2 and a partner gene on either chromosome X (chrX) or an autosome. It remains unknown what types of rearrangements underlie TFE3 fusions, whether fusions can arise from both the active (chrXa) and inactive X (chrXi) chromosomes, and whether TFE3 fusions from chrXi translocations account for the female predominance of tRCC. To address these questions, we performed haplotype-specific analyses of chrX rearrangements in tRCC whole genomes. We show that TFE3 fusions universally arise as reciprocal translocations and that oncogenic TFE3 fusions can arise from chrXi:autosomal translocations. Female-specific chrXi:autosomal translocations result in a 2:1 female-to-male ratio of TFE3 fusions involving autosomal partner genes and account for the female predominance of tRCC. Our results highlight how X chromosome genetics constrains somatic chrX alterations and underlies cancer sex differences.

UNICAB: Cabozantinib in locally advanced or metastatic non‐clear cell renal cell carcinoma post immunotherapy or in those unsuitable for immunotherapy (ANZUP 1802).

428 Background: Rare variant non-clear cell renal cell cancer (nccRCC) have diverse biology and therapeutic response. Immune checkpoint immunotherapy (ICI) can benefit some people with nccRCC, but many experience progression. We sought to test cabozantinib (C) in people with nccRCC refractory to, or unsuitable for ICI. Methods: Eligible participants (pts) had advanced/metastatic nccRCC with good ECOG PS (<2) and either prior treatment with ICI or were unsuitable for ICI due to a contraindicating autoimmune disorder. Pts with urothelial or collecting duct tumour were excluded. Eligible pts started C at 60mg per day with dose modifications as required. Clinical cycles were 28 days and radiological assessment occurred 8-weekly for 12 months. Pts could then continue C via an access program. Results: 33 pts with nccRCC were recruited from Mar 2019 to Dec 2022. Recruitment was influenced by the COVID19 pandemic. Two pts were found ineligible (brain metastasis, concurrent CYP3A4 inducer). Pts tumour histology included papillary type 1 (10), chromophobe (7), papillary type 2 (4), Xp11 translocation (3) and other histologies (7). 24 pts had received prior ICI, mostly nivolumab alone (17) or anti-PD1-antibodies in combination with other agents (anti-CTLA4, anti-TIGIT). Median duration of therapy was 9 cycles. 17 pts ceased for unacceptable toxicity or disease progression and 12 pts completed the 12 months of treatment, with 2 remaining on trial treatment at time of analysis. A partial response was seen 7/31 (22%) pts overall, including 7/24 pts with prior ICI and 0/7 pts unsuitable for ICI. Median treatment duration was 7.5 cycles (range 2-12) in pts with prior ICI treatment, and 11 cycles (range 2-12) in pts unsuitable for ICI. 90% of pts required dose reduction, most often due to fatigue, hypertension, diarrhoea and hand-foot syndrome, with a mean C dose of 46mg/day. No new safety signals were observed. Conclusions: C is an active treatment for people with nccRCC previously treated with ICI, with similar toxicity to previous reports in other cancers. Pts unsuitable for ICI may have poorer outcomes for C therapy in nccRCC. Further follow-up will determine duration of response and overall survival. Clinical trial information: NCT03685448 .

The GATOR2 complex maintains lysosomal-autophagic function by inhibiting the protein degradation of MiT/TFEs

Lysosomes are central to metabolic homeostasis. The microphthalmia bHLH-LZ transcription factors (MiT/TFEs) family members MITF, TFEB, and TFE3 promote the transcription of lysosomal and autophagic genes and are often deregulated in cancer. Here, we show that the GATOR2 complex, an activator of the metabolic regulator TORC1, maintains lysosomal function by protecting MiT/TFEs from proteasomal degradation independent of TORC1, GATOR1, and the RAG GTPase. We determine that in GATOR2 knockout HeLa cells, members of the MiT/TFEs family are ubiquitylated by a trio of E3 ligases and are degraded, resulting in lysosome dysfunction. Additionally, we demonstrate that GATOR2 protects MiT/TFE proteins in pancreatic ductal adenocarcinoma and Xp11 translocation renal cell carcinoma, two cancers that are driven by MiT/TFE hyperactivation. In summary, we find that the GATOR2 complex has independent roles in TORC1 regulation and MiT/TFE protein protection and thus is central to coordinating cellular metabolism with control of the lysosomal-autophagic system.

Identification of Key Differentially Expressed mRNAs, miRNAs, lncRNAs, and circRNAs for Xp11 Translocation Renal Cell Carcinoma (RCC) Based on Whole-Transcriptome Sequencing

We carried out whole transcriptome sequencing (WTS) on the tumor and the matching adjacent normal tissues from five patients having Xp11 translocation renal cell carcinoma (RCC). This was performed in terms of obtaining more understanding of the genomic panorama and molecular basis of this cancer. To examine gene-regulatory networks in XP11 translocation RCC, variance expression analysis was carried out, followed by functional enrichment analysis. Gene Expression Omnibus (GEO) of Xp11 translocation RCC data was used to validate the results. As per inclusion criteria, a total of 1886 differentially expressed mRNAs (DEmRNAs), 56 differentially expressed miRNAs (DEmiRNAs), 223 differentially expressed lncRNAs (DElncRNAs), and 1764 differentially expressed circRNAs (DEcircRNAs) were found. KEGG enrichment study of DEmiRNA, DElncRNA, and DEcircRNA target genes identified the function of protein processing in the endoplasmic reticulum, lysosome, and neutrophil-mediated immunity. Three subnetwork modules integrated from the PPI network also revealed the genes involved in protein processing in the endoplasmic reticulum, lysosome, and protein degradation processes, which may regulate the Xp11 translocation RCC process. The ceRNA complex network was created by Cytoscape, which included three upregulated circRNAs, five upregulated lncRNAs, 24 upregulated mRNAs, and two downregulated miRNAs (hsa-let-7d-5p and hsa-miR-433-3p). The genes as a prominent component of the complex ceRNA network may be key factors in the pathogenesis of Xp11 translocation RCC. Our findings clarified the genomic and transcriptional complexity of Xp11 translocation RCC while also pointing to possible new targets for Xp11 translocation RCC characterization.

Primary Xp11 translocation PEComa of the testis with SFPQ⁃TFE3 rearrangement: a case report and review of the literature

BackgroundPerivascular epithelioid cell neoplasms (PEComas) are a family of mesenchymal tumors with features of both smooth muscle and melanocytic differentiation. A subset of PEComas demonstrate rearrangements involving the TFE3 (Xp11) locus. Xp11 translocation PEComa is a rare neoplasm with special clinicopathological features and a more aggressive behavior. We recently encountered a case of Xp11 translocation PEComa occurring in the testis, with SFPQ⁃TFE3 rearrangement.Case presentationA 57-year-old male touched a mass in his testis incidentally. MRI revealed a 10 mm diameter mass in the right testis. The patient underwent radical orchiectomy. Gross examination revealed a well-demarcated mass from the surrounding testicular tissue. Microscopically, the tumor mainly displayed nested or sheet-like architecture separated by delicate fibrovascular septa. The tumor cells exhibited marked nuclear atypia and pleomorphism. Immunohistochemistry showed that the tumor cells were strongly positive for cathepsin-K, HMB45 and TFE3. Molecular analysis revealed SFPQ⁃TFE3 gene fusion. Thus, it was diagnosed as primary Xp11 translocation PEComa of the testis.ConclusionsThe present case reports primary Xp11 translocation PEComa of the testis for the first time, which to our knowledge has not been described in the literature in this anatomic site, where it could potentially be problematic in diagnosis.

A case of TFE3 translocation renal cell carcinoma with rare morphological features and literature review.

TFE3 translocation renal cell carcinoma (RCC) is a rare tumor that represents approximately 1% of RCC. It was classifed as a member of MiT family translocation RCCs by the World Health Organization in 2016. It is characterized by Xp11 translocation gene fusions involving TFE3. The diagnosis of TFE3 translocation RCC is based on immunohistochemical analysis and TFE3 break apart probes in FISH analysis, rather than histological characteristics and imaging examination. To determine the clinico-pathological, immuno-phenotypic, and cytogenetic characteristics of TFE3 translocation RCC. The clinical data of a 52-year-old-female patient with TFE3 translocation RCC exhibiting rare morphological characteristics was analyzed, and the tumor tissues were probed using histopathological staining, immunohistochemistry, and fluorescence in situ hybridization (FISH). In addition, the relevant literature was reviewed. This case is a TFE3 translocation RCC with rare morphological features. It composed of two types of tumor cells. TFE3 and pax-8 were diffusely and strongly expressed in both tumor cells, and they were partially positive for CAIX, RCC, CK, EMA, CD10, Vim, Melan-A, and p504s. Only 2% of the cells were positive for the proliferation marker Ki-67, and the tumor was negative for CK7, CD117, Inhibin-α, HBM45, and p53. FISH showed a positive signal for TFE3 translocation. This case was a TFE3 translocation RCC with rare morphological features. Through this case report, we emphasize the importance of in situ detection of TFE3 gene translocation and protein in TFE3 translocation RCC.

Morphological spectrum of Xp11. Translocation-Associated Renal Cell Carcinoma in a Developing Country

Objective: to determine unusual morphological features and a panel of immunohistochemical markers to diagnose Xp11 translocation carcinoma.
 Study Design: Retrospective longitudinal study.
 Place and Duration of Study: Shaukat Khanum Memorial Cancer Hospital, Lahore Pakistan, from Jun 2015 to Feb 2020.
 Methodoldogy: We analyzed clinicopathological features, and evaulated intensity and extent of TFE 3 immunoreactivity of 18 cases with suggested diagnosis of xp11 translocation associated renal cell carcinoma from 2015-2020.
 Results: Different morphological pattern includes papillary (8/18, 44%), nested (2/18, 11.1%), alveolar (3/18, 16.7%), nested and papillary (3/18, 16.7%), solid and nested (1/18, 5.6%), cystic and nested (1/18, 5.6%). Four cases show papillary architecture with a linear array of nuclei away from the basement membrane, a pattern seen in SFPQ-TFE3 renal cell carcinoma and NONO-TFE3 renal cell carcinoma. Strong nuclear TFE3 expression was seen in 9/18 (50%) cases. Cathepsin k expression was seen in 6/11 (54%) cases, Ck7 was focal weak positive in 4/12 (25%) cases, PAX8 was positive in 8/8 (100%) cases, and CA IX was focal weak positive in 1/5 (20%) case. According to follow-up data, disease progression was seen in only one case with the low-stage disease. No death was reported due to renal cell carcinoma to date of follow-up.
 Conclusion: We have suggested that young patient age, unusual morphological features and an immunohistochemical panel may help reach the diagnosis in countries with limited resources.

PEComa-like Neoplasms Characterized by ASPSCR1-TFE3 Fusion: Another Face of TFE3-related Mesenchymal Neoplasia.

Identical TFE3-related gene fusions may be found in renal cell carcinoma and mesenchymal neoplasms such as alveolar soft part sarcoma and TFE3-rearranged perivascular epithelioid cell tumor (PEComa). Among mesenchymal neoplasms, the ASPSCR1-TFE3 gene fusion has previously been described only in alveolar soft part sarcoma. We report 3 unusual mesenchymal neoplasms harboring the ASPSCR1-TFE3 gene fusion, the morphologic phenotype of which more closely matches PEComa rather than alveolar soft part sarcoma. All 3 neoplasms occurred in females ranging in age from 18 to 34 years and were located in the viscera (kidney, bladder, and uterus). All 3 contained nests of epithelioid cells bounded by fibrovascular septa. However, all were associated with hyalinized stroma, tight nested architecture, mixed spindle cell and epithelioid pattern, clear cytoplasm, and lacked significant discohesion. Overall, morphologic features closely resembled PEComa, being distinct from the typical alveolar soft part sarcoma phenotype. While none of the neoplasms labeled for HMB45, cytokeratin, or PAX8 all showed positivity for TFE3 and cathepsin K, and all except 1 were positive for smooth muscle actin. One patient developed a liver metastasis 7 years after nephrectomy. These cases bridge the gap between 2 TFE3-rearranged neoplasms, specifically alveolar soft part sarcoma and Xp11 translocation PEComa, highlighting the relatedness and overlap among Xp11 translocation neoplasms. While most TFE3-rearranged neoplasms can be confidently placed into a specific diagnostic category such as alveolar soft part sarcoma, PEComa, or Xp11 translocation renal cell carcinoma, occasional cases have overlapping features, highlighting the potential role that the cell of origin and the specific gene fusion play in the phenotype of these neoplasms.

Translocation carcinomas of the kidney.

The MiT subfamily of transcription factors includes TFE3, TFEB, TFEC, and MITF. Gene fusions involving two of these transcription factors have been well-characterized in renal cell carcinoma (RCC). The TFE3-rearranged RCC (also known as Xp11 translocation RCC) was first officially recognized in the 2004 World Health Organization (WHO) renal tumor classification. The TFEB-rearranged RCC, which typically harbor a t(6;11)(p21;q12) translocation which results in a MALAT1-TFEB gene fusion, were first officially recognized in the 2016 WHO renal tumor classification. These two subtypes of translocation RCC have many similarities. Both disproportionately involve young patients, although adult translocation RCC overall outnumber pediatric cases. Both often have unusual and distinctive morphologies; the TFE3-rearranged RCCs frequently have clear cells with papillary architecture and abundant psammoma bodies, while the TFEB-rearranged RCCs frequently have a biphasic appearance with both small and large epithelioid cells and nodules of basement membrane material. However, the morphology of these two neoplasms can overlap, with one mimicking the other or other more common renal neoplasms. Both of these RCC underexpress epithelial immunohistochemical markers, such as cytokeratin and epithelial membrane antigen, relative to most other RCC. Unlike other RCC, both frequently express the cysteine protease cathepsin k and often express melanocytic markers like HMB45 and Melan A. Finally, TFE3 and TFEB have overlapping functional activity as these two transcription factors frequently heterodimerize and bind to the same targets. Therefore, these two neoplasms are now grouped together under the heading of "MiT family translocation RCC." Approximately 50 renal cell carcinomas with gene fusions involving the anaplastic lymphoma kinase (ALK) gene have now been reported. While those with a Vinculin-ALK fusion have distinctive features (predilection to affect children with sickle cell trait and to show solid architecture with striking cytoplasmic vacuolization), other ALK-fusion RCCs have more varied clinical presentations and pathologic features. This review summarizes our current knowledge of these recently described RCC.

Autophagy in Xp11 translocation renal cell carcinoma: from bench to bedside.

Xp11 translocation renal cell carcinoma (tRCC) characterized by the rearrangement of the TFE3 is recently identified as a unique subtype of RCC that urgently requires effective prevention and treatment strategies. Therefore, determining suitable therapeutic targets and fully understanding the biological significance of tRCC is essential. The importance of autophagy is increasingly acknowledged because it shows carcinogenic activity or suppressor effect. Autophagy is a physiological cellular process critical to maintaining cell homeostasis, which is involved in the lysosomal degradation of cytoplasmic organelles and macromolecules via the lysosomal pathway, suggesting that targeting autophagy is a potential therapeutic approach for cancer therapies. However, the underlying mechanism of autophagy in tRCC is still ambiguous. In this review, we summarize the autophagy-related signaling pathways associated with tRCC. Moreover, we examine the roles of autophagy and the immune response in tumorigenesis and investigate how these factors interact to facilitate or prevent tumorigenesis. Besides, we review the findings regarding the treatment of tRCC via induction or inhibition of autophagy. Hopefully, this study will shed some light on the functions and implications of autophagy and emphasize its role as a potential molecular target for therapeutic intervention in tRCC.

Ipilimumab + nivolumab in people with rare variant renal cell carcinoma refractory to nivolumab alone: Part 2 of UNISON (ANZUP 1602) nivolumab then ipilimumab + nivolumab in advanced non-clear cell renal cell carcinoma.

4565 Background: Immunotherapy targeting PD1 is active across many cancers, but many people are failed by PD1 inhibition alone. UNISON (ANZUP 1602/NCT03177239) has previously reported the activity and outcomes of nivolumab monotherapy in people with nccRCC (OTRR 17%, PFS6 45%; part 1), and here we report the outcomes of combining ipilimumab (I) and nivolumab (N), in people whose cancers are refractory to N alone (part 2). Methods: Participants (pts) with advanced nccRCC with good performance status (ECOG 0/1), were initially enrolled and took N alone. 41 pts refractory to N were offered the combination I (1mg/kg) + N (3mg/kg) every 3 weeks for up to 4 doses. Pts with disease control after N, or N + I could continue N for up to 1 year. UNISON was powered to distinguish a clinically relevant improvement in objective tumour response rate (OTRR) from 15% to 30% in people taking I+N in part 2. Results: 85 pts were enrolled and received N. 41 pts were refractory to N, were well enough to take I+N, and had a representative spectrum of nccRCC histologies (n=41; papillary 44%, chromophobe 20%, Xp11 translocation 12%, RCC unclassified 7%, other 17%). The median time on treatment was 2.1 months, the median number of doses was 3; median follow up at the time of reporting was 20.3 months. The OTRR of I+N in pts refractory to N was 10% with 1 complete and 3 partial responses. Stable disease was experienced by 36% of pts and disease progression by 52%. The disease control rate at 6 months was 45% (95% CI: 34%, 56%). The median PFS was 2.6 months (95% CI: 2.2, 3.8). The 6 month progression-free survival (PFS) was 25% (95% CI: 13-39). Only 14% of patients were free of progression at 12 months. The safety of I+N appeared similar to previous reports. 68% of pts experienced serious adverse events, 34% treatment related SAE. One pt died from refractory pneumonitis. 11 pts (27%) experienced treatment delays or permanent treatment discontinuation. Conclusions: The primary endpoint of the study was not met. A minority of pts with nccRCC refractory to nivolumab derive benefit from combination I+N but many pts remain refractory to immunotherapy. No new safety issues were identified. More effective therapeutic options are needed for people with rare variant renal cell carcinoma. Clinical trial information: NCT03177239.

Nuclear translocation of ASPL-TFE3 fusion protein creates favorable metabolism by mediating autophagy in translocation renal cell carcinoma.

The ASPL-TFE3 fusion gene, resulting from t(X;17)(p11.2;q25.3), is one of the most commonly identified fusion genes in Xp11 translocation renal cell carcinoma (tRCC). However, its roles and underlying mechanism in RCC development are not yet clear. Here, we identified ASPL-TFE3 fusion as the most common tRCC subtype in a Chinese population (29/126, 23.03%). This fusion protein translocated into the nucleus and promoted RCC cell proliferation both in vitro and in vivo. Mechanistically, the fusion protein transcriptionally activated the lysosome-autophagy pathway by binding to the promoters of lysosome-related genes. Autophagy, activated by ASPL-TFE3, enabled RCC cells to escape energy stress by promoting the utilization of proteins and lipids. Moreover, we found that the ASPL-TFE3 fusion escaped regulation by the classic mTOR-TFE3 signal and instead activated phospho-mTOR and its downstream targets. Finally, targeting both autophagy and the mTOR axis resulted in a greater antiproliferative effect than single pathway inhibition. In summary, these results confirmed the ASPL-TFE3 fusion as a master regulator of metabolic adaptation mediated by autophagy in tRCC. The simultaneous manipulation of autophagy and the mTOR axis may represent a novel treatment strategy for ASPL-TFE3 fusion RCC.

UNISON - nivolumab then ipilimumab + nivolumab in advanced non-clear cell renal cell carcinoma (ANZUP 1602): Part 1—Nivolumab monotherapy.

325 Background: Immune checkpoint inhibitors (ICI) are active in many cancers, but people with rare variant, non clear-cell renal cell carcinoma (nccRCC) have been excluded from most clinical trials in RCC. UNISON (NCT03177239) aimed to test 2 hypotheses; the activity of nivolumab in nccRCC (Part 1), and the benefit of adding ipilimumab to nivolumab, in people whose cancers progress on nivolumab (Part 2). Methods: 83 participants (pts) with advanced nccRCC with good (ECOG0/1) performance status, were enrolled including papillary type 1 (17%), papillary type 2 (28%), chromophobe (18%), Xp11 translocation (6%), hereditary leiomyomatosis renal cell carcinoma syndrome-associated renal cell carcinoma (6%), RCC unclassified (10%) and other (15%) histological subtypes. Participants took nivolumab (N) 240mg every two weeks in Part 1 in total. If they experienced progression and remained eligible they could take N (3mg/kg) plus ipilimumab (I; 1mg/kg) every 3 weeks for up to 4 doses (Part 2). Pts with disease control after N or N + I could continue N for up to 1 year. UNISON was powered to distinguish a clinically-relevant improvement in objective tumor response rate (OTRR) from 15% to 30% in people taking N+I in Part 2 in pts whose cancers were refractory to single-agent first-line N. Here we report results of Part 1. Results: Pts experience of N appeared similar to previous reports, with most experiencing mild adverse events. 12 treatment related SAE occurred in 11 patients (13%). 14 pts (17%) experienced treatment delays, or permanent treatment discontinuation (10%). The median time on treatment was 5.1 months. The OTRR was 17% with 3 complete responses and 11 partial responses. The median duration of response was 21 months. Stable disease occurred in 49% of pts and disease progression in 34%. The disease control rate at 6 months was 45% (95% CI: 34%, 56%). The median PFS was 4.0 months (95% CI: 3.6, 7.4). The 6 month progression-free survival (PFS) was 45% (95% CI: 34-55) and the 12 months PFS was 30% (95% CI: 21%, 40%). Conclusions: Pts with nccRCC treated with N experience similar adverse events compared to pts with other cancers. A substantial minority of people with nccRCC derive benefit, but many pts have cancers refractory to anti-PD1, similar to other reports. The activity of I and N in this PD1-refractory population is of considerable interest and will be reported at a later date. Clinical trial information: NCT03177239 .

BAP1-Mutated Clear Cell Renal Cell Carcinoma.

While aberrations in the VHL gene and chromosome 3p resulting in clear cell renal cell carcinoma (CCRCC) are well established, we know that additional mutations in chromatin remodeling genes PBRM1, SETD2, and BRCA1-associated protein 1 (BAP1) contribute to pathogenesis in some cases. Given the known aggressive clinical behavior of BAP1-mutated CCRCC, we sought to define the pathologic phenotype of BAP1-mutated CCRCC. We identified 14 cases of molecularly proven BAP1-mutated CCRCC and investigated their clinicopathologic features. BAP1-mutated CCRCC frequently showed papillary, tubulopapillary, or expanded nested architecture; demonstrated granular to diffusely eosinophilic cytoplasm with prominent eosinophilic globules; and contained high-grade nuclei. This morphology demonstrates significant overlap with Xp11 translocation renal cell carcinoma (RCC). Immunohistochemistry notably demonstrates loss of BAP1 expression in almost all tumors, in addition to strong p504S expression. A conventional CCRCC component was frequently present adjacent to the characteristic BAP1 areas and showed retained BAP1 expression and only patchy p504S. Approximately two-thirds of BAP1-mutated CCRCCs were stage pT3, renal vein invasion was common, and 50% developed metastases. Herein, we describe the histologic and immunohistochemical findings in BAP1-mutated CCRCC, which has important implications for utilization of molecular testing, prognosis, future therapeutics, and distinction from other RCC subtypes such as Xp11 translocation RCC.

Xp11 translocation renal cell carcinoma with morphological features mimicking multilocular cystic renal neoplasm of low malignant potential: a series of six cases with molecular analysis

AimsXp11 translocation renal cell carcinoma (RCC) is a distinctive subtype of RCC with TFE3 (Transcription Factor Binding to IGHM Enhancer 3) gene rearrangement. The gross features in most Xp11 translocation...

Malignant melanotic Xp11 neoplasms exhibit a clinicopathologic spectrum and gene expression profiling akin to alveolar soft part sarcoma: a proposal for reclassification.

The classification of the distinct group of mesenchymal neoplasms, first described as 'Xp11 translocation perivascular epithelioid cell tumor (PEComa)' and for which the term 'melanotic Xp11 neoplasm' or 'Xp11 neoplasm with melanocytic differentiation' has recently been proposed, remains challenging and controversial. We collected 27 melanotic Xp11 neoplasms, the largest series to date, for a comprehensive evaluation. Fourteen of the cases, together with eight alveolar soft part sarcomas (ASPS), nine conventional PEComas and a control group of seven normal tissues were submitted to RNA sequencing. Follow-up available in 22 patients showed 5-year overall survival and 5-year disease-free survival of 47.6 and 35.7%, respectively, which were similar to ASPS and significantly worse than conventional PEComa. Univariate analysis of location (occurring in the kidney versus not kidney), infiltrative growth pattern, nuclear pleomorphism, mitotic activity ≥2/50 high-power fields (HPF), necrosis and lymphovascular invasion were found to be associated with overall survival and/or disease-free survival. Multivariate analysis identified that location was the only factor found to independently correlate with disease-free survival. More importantly, RNA sequencing-based clustering analysis segregated melanotic Xp11 neoplasm and ASPS from other tumors, including conventional PEComa and Xp11 translocation renal cell carcinoma, and formed a compact cluster representative of the largely similar expression signature. Here we clearly define the true biologic nature of melanotic Xp11 neoplasms which are distinctive malignant mesenchymal tumors, rather than simply PEComa variants with occasionally unpredictable behavior. Meanwhile, melanotic Xp11 neoplasm and ASPS more likely represent phenotypic variants of the same entity, which is distinct from conventional PEComa and Xp11 translocation renal cell carcinoma. Based on these important findings, melanotic Xp11 neoplasm might be reclassified into a distinctive entity together with ASPS, independent from PEComa, in future revisions of the current WHO categories of tumors of soft tissue and bone for the improved reclassification. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

PD-L1 expression and infiltration by CD4+ and FoxP3+ T cells are increased in Xp11 translocation renal cell carcinoma and indicate poor prognosis.

Interaction between programmed death-1 ligand (PD-L1) and its receptor programmed death 1 (PD-1) on T cells inactivates antitumour immune responses. PD-L1 expression has been associated with poor prognosis in renal cell carcinoma (RCC) and predicts adverse outcome. This study was designed to evaluate the impact of PD-L1 expression and the immune microenvironment on the clinical outcome in Xp11 translocation renal cell carcinoma (TRCC) and, therefore, their potential relevance as prognostic biomarkers. The present retrospective analysis investigated expression of PD-L1 and immune cells CD8, CD4, CD3, forkhead box protein 3 (FoxP3) and PD-1 in TRCC compared to other types of RCC. FFPE specimens were collected between 2011 and 2017 from 311 patients who underwent nephrectomy at our institution for RCC. Specimens were immunostained for PD-L1, CD8, CD4, CD3, FoxP3 and PD-1, and an outcome analysis was conducted. PD-L1 expression rate was highest in TRCC (68%, 16 of 25), followed by mucinous tubular and spindle cell RCC and collecting duct carcinoma (33%, one of three), papillary RCC (27%, seven of 26), clear cell RCC (16%, 29 of 233), chromophobe RCC (11%, two of 18) and multilocular cystic RCC (0%, none of three). In TRCC, PD-L1 expression was associated with poor recurrence-free survival (RFS) (P=0.041). The CD4high and FoxP3high groups showed a significantly shorter RFS (P=0.05 and P=0.031, respectively) compared to CD4low and FOXPlow groups. PD-L1 expression was higher in TRCC than in other types of RCC. High PD-L1 tumour cell expression and tumour infiltration by CD4+ and FoxP3+ immune cells were associated with poor RFS in TRCC.

UNISON: Nivolumab then ipilimumab + nivolumab in advanced nonclear cell renal cell carcinoma (ANZUP 1602).

TPS768 Background: Renal cell carcinomas (RCC) are predominantly the clear cell (cc) subtype, with a unique biology, characterized by sensitivity to angiogenesis inhibition. However vascular endothelial growth factor-tyrosine kinase inhibitors elicit modest responses in people with rare variant non-clear cell (ncc) RCC. Immune checkpoint inhibitors (ICI) are active against many cancers, but people with rare variant nccRCC have been excluded from frontline trials despite experiencing a more aggressive disease course and poorer prognosis compared to those with ccRCC. UNISON (NCT03177239) aims to test 2 ideas; the activity of ICI in nccRCC, and the novel sequencing strategy of anti-programmed cell death protein (PD)1 immunotherapy, followed by the combination of anti-PD1 and anti-cytotoxic T-lymphocyte-associated protein (CTLA)4 blockade, in people failed by single agent treatment. Methods: This single-arm, two-part trial recruits people of good performance status suffering metastatic or locally advanced unresectable rare variant nccRCC, including but not limited to papillary (type 1/2), chromophobe, sarcomatoid, Xp11 translocation, collecting duct, and unclassified histological subtypes. Participants are offered fixed dose nivolumab at 240mg every two weeks in Part 1 of the trial. If they experience progressive disease, eligible participants may proceed to Part 2 consisting of nivolumab (3mg/kg) plus ipilimumab (1mg/kg) every 3 weeks for up to 4 doses. People experiencing disease control after single-agent or combined ICI are eligible to continue treatment for up to 1 year. UNISON is powered to distinguish a clinically non-relevant objective tumor response rate (OTRR) of 15% in people taking combination ICI whose cancers are refractory to single-agent PD1, versus a clinically-relevant OTRR of 30% at 5% level of significance with 80% power. 85 participants were recruited in Part 1, on the assumption that 55% of those entering Part 1 will be eligible for inclusion in Part 2. Enrolment commenced in November 2017 and was completed ahead of schedule in September 2019. Of the 48 participants projected to experience progression on anti-PD1 immunotherapy, 36 have so far commenced combination ICI in Part 2. Clinical trial information: NCT03177239.

Comparative Clinicopathologic Characteristics and Outcomes of Paediatric and Adult Xp11 Translocation Renal Cell Carcinomas: a Retrospective Multicentre Study in China

This study aimed to compare the clinicopathologic features and prognosis in patients with Xp11 translocation renal cell carcinomas (RCCs). In total, 8083 RCCs were screened at five centres from January 2007 to December 2018, including 8001 adults (≥18 years) and 82 children (<18 years). Finally, 73 adults and 17 children were identified as Xp11 translocation RCCs, accounting for 1.1% (90 of 8083) of the RCCs. However, 4 children and 1 adult were excluded because of loss to follow-up when performing the survival analysis. The proportion of paediatric and adult Xp11 translocation RCCs was 20.7% (17 of 82) and 0.9% (73 of 8001) of RCCs, respectively, and the incidence in children and adults was significantly different (P < 0.01). Lymph node positivity (LN+) most commonly occurred in children (58.8%) compared with adults (28.8%; P = 0.02), but children with LN+ showed significantly higher five-year overall survival and progression-free rates (OS: 75.0%; PFS: 64.8%) than adult patients (OS: 40.3%; PFS: 0%) (log-rank PPFS < 0.01; POS = 0.04). Multivariable analysis indicated that local lymph node metastasis was associated with both PFS (HR = 0.10; 95% CI 0.02–0.51; P = 0.01) and OS (HR = 0.11; 95% CI 0.01–0.98; P = 0.04) in adults. Adult patients with LN+ may indicate a worse prognosis than paediatric patients.

Cytopathology of Xp11 translocation renal cell carcinoma: a report of 5 cases

Xp11.2 translocation-associated RCC (Xp11RCC) defined by molecular alterations involving TFE3 genetic rearrangements constitutes a large percentage of primary renal neoplasms in children, but less than 4% of adult cases. Fewer than 10 single case reports constitute the English cytopathology literature regarding this neoplasm. Our objective is to describe and illustrate the cytopathology of this uncommon renal neoplasm from a series of 5 cases using cytologic imprints, effusion specimens, and fine-needle aspiration (FNA) cytology. Review was made of our cytopathology and surgical pathology databases. FNA biopsy smears and imprint smears were performed using a standard technique. Effusion samples were processed using liquid-based slides. Five cytologic specimens from 4 patients with histopathologically confirmed Xp11RCC were identified (mean age: 36 years) over a period of 7 years. All cases contained large cells with voluminous amounts of vacuolated cytoplasm arranged in non-descript clusters and as single forms. A "tigroid" pattern consisting of linear strips of detached cytoplasm was seen in both imprint smear cases and the single FNA case. Psammomatous calcifications, true papillary structures, and hyaline globules were absent in all cases. Four examples were diagnosed as Xp11RCC, but 3 represented metastatic disease, and 1 was diagnosed using both cytology and core needle tissue histopathology. The remaining case was diagnosed nonspecifically as a clear cell malignant neoplasm. The cytopathologic features of Xp1RCC are relatively nonspecific, and overlap with other renal cell carcinoma subtypes. A definitive diagnosis is only possible with ancillary immunohistochemistry with or without additional TFE3 fluorescence in situ hybridization.