. 2026 May 11;489(3):669–680. doi: 10.1007/s00428-026-04576-1

Comprehensive analysis of six MED15::TFE3 renal cell carcinomas including two novel solid MED15::TFE3 renal cell carcinomas, highlighting their morphologic, immunohistochemical and molecular differences from their cystic counterparts

Jung Woo Kwon ^1,^✉, Sarah Mae Lammert ¹, Hayley Zullow ¹, Peng Wang ¹, Melissa Yuwono Tjota ¹, Tatjana Antic ¹

PMCID: PMC13582055 PMID: 42113263

Abstract

In 2017, the first case of TFE3-rearranged renal cell carcinoma (RCC) with MED15 as a novel fusion partner gene was reported. Since then, vast majority of MED15::TFE3 RCCs were reported to have characteristic extensively cystic appearance, with the septa being lined by tumor cells with optically clear cytoplasm and inconspicuous nucleoli, morphologically mimicking multilocular cystic renal neoplasm of low malignant potential and clear cell RCC with extensive cystic changes. IHC stains are helpful in such diagnostic scenario, as MED15::TFE3 RCCs are negative for carbonic anhydrase IX (CAIX) and are positive for melanocytic markers and TFE3. However, the current MED15::TFE3 RCCs case series includes two solid MED15::TFE3 RCCs, which are morphologically, immunohistochemically and molecularly different from the conventional MED15::TFE3 RCCs that are extensively cystic. One case is purely solid with nests of tumor cells with clear cytoplasm mimicking clear cell RCC. This purely solid MED15::TFE3 RCC is positive for TFE3, focally positive for CAIX with box-like membranous staining, and negative for Melan A. Another case is mostly solid and tubulopapillary with minor cystic components, is positive for TFE3, and negative for Melan A and CAIX. The non-cystic MED15::TFE3 RCCs also have unique fusion transcripts that are different from those seen in the conventional MED15::TFE3 RCCs. The phenotypic variation of MED15::TFE3 RCCs may be due to the property of the fusion transcripts, although additional studies are required to validate this finding.

Keywords: MED15::TFE3 renal cell carcinoma, TFE3-rearranged renal cell carcinoma, RNA sequencing, Renal cell carcinoma

Introduction

TFE3-rearranged renal cell carcinoma (RCC) is a rare subtype of RCC that is defined by fusion of the TFE3 gene on chromosome Xp11.23 with one of many reported partner genes, with the three most common being PRCC, ASPSCR1 and SFPQ [1]. Morphologically, TFE3-rearranged RCCs are classically described to have papillary architecture composed of tumor cells with variably clear cytoplasm and are frequently associated with psammoma bodies. Immunohistochemically, TFE3-rearranged RCCs occasionally (depending on partner gene) show melanocytic marker positivity and the strong nuclear overexpression of TFE3 immunohistochemical (IHC) stain [2]. However, TFE3-rearranged RCC can have diverse morphologic features beyond its classic morphology, and its morphological features can widely vary depending on its fusion partner gene [1–9], often creating diagnostic challenges to pathologists.

In 2017, Classe et at reported the first case of TFE3-rearranged RCC with MED15 as a novel fusion partner gene, and the tumor was described to be partially cystic [10]. Since then, numerous case reports and small case series have described over 30 cases of MED15::TFE3 RCCs [8–21]. Vast majority of MED15::TFE3 RCC is reported to have its characteristic extensively cystic appearance, with the cystic septa being lined by tumor cells with optically clear cytoplasm and inconspicuous nucleoli, and scattered psammomatous calcifications are often present [8, 10–17, 19, 20]. Due to its extensively cystic appearance and the tumor cells with optically clear cytoplasm, MED15::TFE3 RCCs have significant morphologic overlaps with multilocular cystic renal neoplasm of low malignant potential (MCN-LMP), clear cell renal cell carcinoma (CCRCC) with extensive cystic changes, and clear cell papillary renal cell tumor with cystic changes (CCPRCT), and they could be easily misdiagnosed if a reviewing pathologist is unaware of the differential diagnosis in the setting of extensively cystic renal neoplasm lined by optically clear cells. IHC stains are often helpful in such diagnostic scenario, as MED15::TFE3 RCCs are negative for carbonic anhydrase IX (CAIX), are positive for melanocytic markers, and have TFE3 nuclear overexpression.

However, the current MED15::TFE3 RCCs case series reports two novel cases of MED15::TFE3 RCCs with none-to-minor cystic component, which may be due to their unique underlying molecular features that were not previously reported in conventional extensively cystic MED15::TFE3 RCCs. This series aims to provide comprehensive morphologic, immunohistochemical and molecular analysis of six MED15::TFE3 RCCs, which include four cases that were previously reported by Doytcheva et al. [14] with additional analysis and follow up, and compare the current cases with other MED15::TFE3 RCCs that have been reported in literature to this date.

Methods

Case selection, clinical data collection, and review of histopathology

The retrospective search of the University of Chicago department of Pathology archives from 2005 and 2025 resulted in identification of six MED15::TFE3 RCCs, four of which were previously published by Doytcheva et al. [14]. Clinicopathologic data was collected from electronic medical records. All the cases were reviewed by two expert genitourinary pathologists. The study was approved by the University of Chicago Institutional Review Board.

Immunohistochemistry

Immunohistochemical (IHC) stains were performed on selected paraffin blocks using autoimmunostainers (Leica BOND-III; Leica Biosystems, Buffalo Grove, IL, USA and BenchMark XT Ventana; Roche, Tucson, AZ, USA), with appropriate controls. IHC staining was performed for CAIX (CAIX; TH22; Leica Biosystems, Richmond, VA, USA), CK7 (CK7; OV-TL 12/30; Dako, Carpinteria, CA, USA), Melan-A (A103; Dako, Carpinteria, CA), TFE3 (SC-5958; Santa Cruz, CA, USA), and CD10 (NCL-CD10—270; Leica Biosystems, Richmond, VA, USA).

RNA sequencing

Hybrid capture targeted RNA next-generation sequencing (NGS) analysis for gene fusion was performed using the following method. The tumor-rich tissue block was selected for cutting unstained sections. Adequate specimens should contain > 10,000 cells with > 20% of tumor cells. Appropriate number of unstained formalin-fixed paraffin-embedded tissue slides were used for DNA extraction depending on the cellularity on the sections. RNA was extracted using the RNeasy FFPE Kit (Qiagen, Valencia, CA) and quantified using a Qubit fluorometric assay (Thermo Fisher Scientific, FosterCity, CA) adjusted for the percentage of fragments greater than 100 bp using the TapeStation system (Agilent). 300 ng RNA was subjected to library prep using the KAPA stranded RNA-Seq Kit with RiboErase (Kapa Biosystems), followed by quantitation using the KAPA library quantification kit (Kapa Biosystems). Pooled libraries were captured using a panel of biotinylated oligonucleotides (xGen Lockdown probes, IDT). Amplified pooled captured libraries were sequenced in rapid run mode on a NovaSeq 6000 system (Illumina) to produce 2 × 101 bp paired end sequencing reads. Sequence data were aligned to the hg19 human reference transcriptome using STAR aligner [22], and fusions were detected using a combination of in-house developed python software and STAR fusion software. (STAR-fusion: fast and accurate fusion transcript detection from RNA-Seq. software bioRxiv120295. https://doi.org/10.1101/120295).

The assay has been validated in the University of Chicago CLIA-certified Molecular Diagnostic Laboratory to report fusions involving the following genes: NTRK1, NTRK2, NTRK3, FGFR1, FGFR2, FGFR3, ABL1, ABL2, PDGFRA, PDGFRB, CSF1R, JAK2, P2RY8, CRLF2, KMT2A(MLL), EWSR1, TFE3, TFEB, ALK, ROS1 and RET.

DNA sequencing

A representative formalin-fixed, paraffin-embedded block was selected for DNA NGS in the University of Chicago Medicine OncoPlus (UCM-OncoPlus) panel, a hybrid-capture panel targeting 1005 cancer-associated genes of which 168 genes are clinically reported. DNA extraction, DNA quantification, library preparation, and NGS were performed as described [23]. Data analysis was performed using a high-performance computing system (Center for Research Informatics, University of Chicago) using an in-house developed bioinformatics pipeline. CNV Kit14 software with additional in-house intrarun normalization with comparison with a pooled cohort of clinical controls was used to calculate copy number results. The threshold for arm-level copy number changes was an ARM average FC < 0.75 called as deleted and an ARM average FC > 1.5 called as amplified. Somatic variant calls were inspected using Integrated Genomics Viewer (Broad Institute, MIT Harvard, Cambridge, MA). Cosmic and ClinVar were used as additional tools to analyze and confirm detected variants.

Literature review

PubMed (https://pubmed.ncbi.nlm.nih.gov/) was searched for TFE3-rearranged RCCs with MED15::TFE3 fusion that was confirmed by molecular testing techniques (i.e. fluorescence in situ hybridization (FISH), RNA NGS, etc.). Studies that did not have molecular confirmation were excluded.

Results

Clinical features

Clinicopathologic features of the 6 MED15::TFE3 RCCs are summarized in Table 1. Most patients were female (5/6, 83%) and Caucasian (4/6, 67%), with an average age of 46 years (range = 30—63). Tumor size varied greatly (range = 2.1—14.5 cm, average = 5.4 cm). All patients had no lymph nodal or distant metastasis and are alive with no evidence of recurrent/persistent disease based on their most recent follow-up data available for review.

Table 1.

Summarized key clinicopathologic features of the 6 MED15::TFE3 RCCs in the current study

Case #	Age/Sex	Procedure	Size (cm)	Stage	Architecture	Melan A	TFE3	CAIX	CK7	CD10	P504S	Exons Fused	Follow up
1*	37/F	Partial nephrectomy	14.5	pT2bNxMx	Extensively cystic	+	+	-	-	+	+	MED15 exon 8-TFE3 exon 6	NED 67 months
2*	52/F	Partial nephrectomy	1.8	pT1aNxMx	Extensively cystic	+	+	-	-	+	+	MED15 exon 9-TFE3 exon 6	NED 62 months
3*	35/F	Partial nephrectomy	4.5	pT1NxMx	Extensively cystic	+	+	-	-	+	+	MED15 exon 8-TFE3 exon 6	NED 11 months
4*	63/F	Partial nephrectomy	2.1	pT1NxMx	Extensively cystic	+	+	-	-	+	+	MED15 exon 9-TFE3 exon 6	NED 8 months
5	30/M	Radical nephrectomy	3.1	pT3aNxMx	Entirely solid	-	+	+ (focal)	-	+	+	MED15 exon 11-TFE3 exon 7; MED15 mid-intron 11-TFE3 exon 6	NED 5 months
6	61/F	Radical nephrectomy	6.5	pT3aN0Mx	Predominantly tubulopapillary with minor cystic component	-	+	-	-	+	+	MED15 exon 13-TFE3 exon 4	NED 134 months

Open in a new tab

F = Female, M = Male

NED = No evidence of disease

^*Previously published by Doytcheva et al.[14]

Cases 1—4: Conventionally described extensively cystic MED15::TFE3 RCCs

Cases 1—4, previously published by Doytcheva et al. [16], grossly revealed well-circumscribed extensively multiloculated cystic lesion without solid areas. H&E showed extensive cystic architecture with no gross solid areas, which corresponded to their gross appearances (Fig. 1A). The cystic wall had thin fibrous septa with scattered psammomatous calcifications (Fig. 1B). The cystic wall was lined by tumor cells with optically clear cytoplasm and small nuclei with inconspicuous nucleoli (Fig. 1C). Focal microscopic areas showed solid (Fig. 1D) and papillary-appearing proliferation (Fig. 1E), although the tumor cells seen in this area had identical cytologic features to those lining the cystic wall. In some areas, multinucleated tumor cells were identified, although the nuclear features were identical to the adjacent mononuclear tumor cells (Fig. 1F). Tumor necrosis and mitotic figures were not identified. IHC stains with appropriate controls showed that Cases 1—4 were diffusely positive for TFE3 (Fig. 1G), Melan A (Fig. 1H) and PAX8, and negative for CK7 and CAIX.

Fig. 1 — Cases 1—4 showed extensive cystic architecture (A). The cystic wall had thin fibrous septa with scattered psammomatous calcifications (B). The cystic wall was lined by tumor cells with optically clear cytoplasm and small nuclei with inconspicuous nucleoli (C). Focal microscopic areas showed solid (D) and papillary-appearing proliferation (E), although the tumor cells seen in this area had identical cytologic features to those lining the cystic wall. In some areas, multinucleated tumor cells were identified, although the nuclear features were identical to the adjacent mononuclear tumor cells (F). IHC stains showed that all the cases were diffusely positive for TFE3 (G), Melan A (H), CD10 (apical pattern; I), P504S (J) and PAX8, and negative for CK7 and CAIX

RNA sequencing of Cases 1—4 confirmed the presence of MED15::TFE3 fusion transcripts in all cases. The fusion transcript in Cases 1 and 3 showed a connection between exon 8 of MED15 and exon 6 of TFE3. The fusion transcript in Cases 2 and 4 showed a connection between exon 9 of MED15 and exon 6 of TFE3. All fusion transcripts kept the reading frames preserved at the junction points.

Case 5: Novel case of purely solid MED15::TFE3 RCC morphologically mimicking clear cell renal cell carcinoma

Case 5 grossly revealed purely solid yellow-beige multinodular mass with no cystic areas (Fig. 2A-B). H&E revealed a tumor with purely solid nested architecture with areas of hemorrhage (Fig. 2C). No cystic component was seen. The tumor nests were predominantly composed of tumor cells with cleared-out cytoplasm, surrounded by rich thin-walled capillary network (Fig. 2D), highly reminiscent of CCRCC. Tumor cells had uniformly round small-to-medium sized nuclei with inconspicuous nucleoli, and some displayed variable degree of eosinophilia (Fig. 2E). There were also rare foci with degenerative changes, where there were “balloon” cells with ample eosinophilic cytoplasm (Fig. 2F). In these degenerative foci, bizarre eosinophilic multinucleated giant tumor cells with variable intracytoplasmic vacuolation and blue granules/basophilic stippling were also present (Fig. 2G). Tumor necrosis, increased mitotic activity and psammomatous calcifications were not identified.

IHC stains with appropriate controls showed that the tumor had focal (5—10%) box-like membranous staining for CAIX (Fig. 2H), primarily centered around the foci of degeneration/fragmentation. TFE3 IHC stain showed nuclear overexpression (Fig. 2I). Tumor was negative for Melan A (Fig. 2J) and CK7. Additionally, tumor was diffusely positive for CD10 (Fig. 2K) and also showed patchy positivity for P504S (Fig. 2L).

RNA sequencing of Case 5 showed two distinct MED15::TFE3 fusion transcripts. One fusion transcript showed a connection between exon 11 of MED15 and exon 7 of TFE3, and another showed a connection between mid-intron 11 of MED15 and middle of exon 6 of TFE3. Both transcripts kept the reading frames preserved at the junction points.

DNA sequencing showed no pathogenic mutations in VHL or other RCC-defining genes (i.e. TSC1, TSC2, MTOR). No significant copy number changes were identified. There was no microsatellite instability.

Case 6: Predominantly tubulopapillary MED15::TFE3 RCC with minor cystic components

Case 6 grossly revealed a fleshy solid mass with focal cystic changes that showed excrescences and polypoid architecture. (Fig. 3A). H&E revealed tumor cells forming a tightly packed tubulopapillary architecture forming a solid configuration with scattered psammomatous calcification (Fig. 3B) and minor cystic components (Figs. 3C and 3D). The minor cystic component showed thin fibrous septa lined by tumor cells with clear cytoplasm with occasional eosinophilic granularity (Fig. 3E), highly reminiscent of the morphologic features seen in Cases 1—4. In areas with tubulopapillary architecture, tumor cells were predominantly eosinophilic with occasional clear cytoplasm (Fig. 3F). Tumor cells had round small-to-medium sized nuclei with inconspicuous nucleoli, and it occasionally showed amorphous material in the lumen that was reminiscent of corpora amylacea in prostatic lumina (Fig. 3G). In some areas, there were multinucleated giant tumor cells with syncytial appearance, although their nuclei seemed similar to the adjacent mononuclear tumor cells (Fig. 3H). Tumor necrosis and mitotic figures were not identified.

IHC stains with appropriate controls showed that the tumor was positive for TFE3 (Fig. 3I), and negative for Melan A (Fig. 3J), CAIX and CK7. Additionally, tumor was positive for CD10 (apical pattern; Fig. 3K) and also showed patchy positivity for P504S (Fig. 3L).

RNA sequencing of Case 6 confirmed the presence of a MED15::TFE3 fusion transcript, which showed a connection between exon 13 of MED15 and exon 4 of TFE3. The fusion transcript kept the reading frames preserved at the junction points.

Discussion

Since Classe et al. first reported a case of TFE3-rearranged RCC with MED15 as a novel fusion partner gene in 2017 [10], a total of 33 cases (excluding the 6 cases in the current study) of molecularly confirmed MED15::TFE3 RCC has been reported in literature to this date [8–21], and their key features are summarized in Table 2. Among the case reports/series that reported architectural patterns of their tumors (excluding a total of 4 cases by Pei et al. [9], Harada et al. [17] and Achom et al. [21]), all 29 cases have been described to have a significant amount of cystic component. In fact, 86% (25 of 29 cases) of MED15::TFE3 RCCs have been described to be extensively or exclusively cystic. The remaining 14% (4 of 29 cases) of MED15::TFE3 RCCs were described to be partially cystic with other mixed architectural components, such as solid, papillary, tubular and acinar patterns [8, 10, 12]. Interestingly, all reported cases of MED15::TFE3 RCCs that were stained for Melan A immunostain showed at least some positivity (12/12), although some cases that were stained for HMB45 and MART-1 immunostains showed negativity.

Table 2.

Summarized key clinicopathologic features of all the reported MED15::TFE3 RCCs in the literature

Study	Age/Sex	Size (cm)	Architecture	Exons fused	Outcome	Melanocytic marker
Classe et al. [10]	34/F	9.5	Mixed and cystic	MED15 exon 9-TFE3 exon 6	NED 48 months	N/A
Wang et al. [8]	42/M	1.5	Extensively cystic	N/A	NED	Melan-A +
	41/M	9	Acinar, tubular & papillary*	N/A	Alive; Lung metastases after 15 years	Melan-A +
	54/F	4	Extensively cystic	N/A	NED	Melan-A +
	45/F	4.5	Extensively cystic	N/A	NED	Melan-A +
	30/F	5	Cystic, papillary, solid	N/A	NED	Melan-A +
Ye et al. [12]	35/F	5	Solid and cystic	MED15 exon 11-TFE3 exon 6	N/A	Neg (Melan-A & HMB45)
Pei et al. [9]	22/F	2	N/A	N/A	N/A	Melan-A 25% +, HMB45 -
Song et al. [13]	40/M	4	Extensively cystic	N/A	NED 46 months	Mart-1 +
	51/F	3.6	Extensively cystic	N/A	NED 38 months	Negative (Mart-1)
	49/M	3	Extensively cystic	N/A	NED 54 months	Negative (Mart-1)
	47/M	5.8	Extensively cystic	N/A	NED 8 months	Negative (Mart-1)
	28/F	3	Extensively cystic	N/A	NED 19 months	Mart-1 +
	32/F	3.1	Extensively cystic	N/A	NED 56 months	Mart-1 +
Harada et al. [17]	N/A	N/A	N/A	N/A	N/A	N/A
Argani et al. [11]	74/F	6	Extensively cystic	N/A	N/A	Melan-A +, HMB45 -
	40/F	3	Extensively cystic	N/A	N/A	Melan-A +, HMB45 -
Cai et al. [19]	71/F	3.8	Cystic, multiloculated	MED15 exon 9-TFE3 exon 6	NED 33 months	Melan-A +
Sun et al. (8 cases) [20]	Median age (range): 37.5 (18—70); 6 females, 2 males
	TFE3—06	5.9	Extensively cystic	N/A	NED	N/A
	TFE3—21	4.1	Extensively cystic	N/A	NED	N/A
	TFE3—27	4.5	Extensively cystic	N/A	NED	N/A
	TFE3—31	3.3	Extensively cystic	N/A	NED	N/A
	TFE3—38	13.4	Extensively cystic	N/A	NED	N/A
	TFE3—51	5.8	Extensively cystic	N/A	NED	N/A
	TFE3—60	6.5	Extensively cystic	N/A	NED	N/A
	TFE3—63	6	Extensively cystic	N/A	NED	N/A
Yin et al. [14]	29/F	9.3	Extensively cystic	MED15 exon 8-TFE3 exon 6	NED 26 months	Melan-A +, HMB45 -
	35/F	4.8	Extensively cystic	MED15 exon 7-TFE3 exon 6	NED 6 months	Melan-A +, HMB45 -
Mladenovic et al. [15]	36/F	4.7	Exclusively cystic	N/A	NED 13 months	Melan-A + (patchy)
Deng et al. [16]	27/F	6.8	Cystic	N/A	NED 71 months	N/A
	17/F	16	Cystic	N/A	NED 47 months	N/A
Achom et al. [21]	TRCC_10 (age N/A; female)	N/A	N/A	N/A	N/A	N/A
	TRCC_13 (age N/A; female)	N/A	N/A	N/A	N/A	N/A
Current study	37/F (Case 1)**	14.5	Extensively cystic	*MED15* *exon 8-TFE3* exon 6**	NED 67 months	Melan-A +
	52/F (Case 2)**	1.8	Extensively cystic	*MED15* *exon 9-TFE3* exon 6**	NED 62 months	Melan-A +
	35/F (Case 3)**	4.5	Extensively cystic	*MED15* *exon 8-TFE3* exon 6**	NED 11 months	Melan-A +
	63/F (Case 4)**	2.1	Extensively cystic	*MED15* *exon 9-TFE3* exon 6**	NED 8 months	Melan-A +
	30/M (Case 5)	3.1	Entirely solid	*MED15* *exon 11-TFE3* exon 7; MED15 mid-intron 11-TFE3 exon 6**	NED 5 months	Negative (Melan A)
	61/F (Case 6)	6.5	Solid & papillary with minimal cystic component	*MED15* *exon 13-TFE3* exon 4**	NED 134 months	Negative (Melan A)

Open in a new tab

^*This is the morphology of the primary kidney tumor (case 19) described in the main text by Wang et al. [8]. Lung metastasis of the tumor that developed later in the same patient had solid architecture

^**Previously published by Doytcheva et al.[14]

In the current study, four of the six cases showed conventional features of MED15::TFE3 RCC that was previously reported: extensively cystic appearance morphologically mimicking MCN-LMP, CCRCC with extensive cystic changes, and clear cell papillary renal cell tumor (CCPRCT) with cystic appearance. As they have significant morphologic overlap, one’s threshold for ordering IHC stains should be low. A panel of CAIX, CK7, melanocytic markers such as HMB45, Melan A, and MART-1, and TFE3 could be useful, as cystic MED15::TFE3 RCCs are negative for CAIX (which is positive in MCN-LMP, CCRCC, and CCPRCT) and CK7 (which is always positive in CCPRCT and also variably positive in MCN-LMP), are positive for melanocytic markers (which are negative in MCN-LMP, CCRCC, and CCPRCT), and have TFE3 nuclear overexpression. In particular, CAIX negativity should raise suspicion for MED15::TFE3 RCC in cystic lesions with clear cells, as MCN-LMP, CCRCC, and CCPRCT, the main differential diagnosis in this diagnostic scenario, are all diffusely positive for CAIX.

However, the remaining two MED15::TFE3 RCCs had none-to-minimal cystic components, with one case being the first novel reported case of purely solid MED15::TFE3 RCC. The purely solid case (Case 5) of MED15::TFE3 RCC in the current study showed striking morphologic mimicry of CCRCC, as it is mostly composed of solid nests of tumor cells with clear cytoplasm that are surrounded by thin-walled capillaries. It had unusual degenerative areas that showed multinucleated giant tumor cells and bizarre “balloon” cells, although the multinucleated giant cells and enlarged eosinophilic tumor cells can be seen in clear cell renal cell carcinoma, with the latter more frequently seen in high grade clear cell renal cell carcinomas, particularly those with BAP1 mutation [24–31]. Additionally, this purely solid MED15::TFE3 RCC did not have any psammomatous calcifications, which was present in all other MED15::TFE3 RCCs in the current study. However, the presence of the psammomatous calcifications would not necessarily distinguish this tumor from CCRCCs as some CCRCCs are reported to have psammomatous calcifications [28]. Presence of the blue granules/basophilic stippling in this purely solid MED15::TFE3 RCC is however unreported in CCRCC and is a feature that was thought to be primarily linked to eosinophilic solid and cystic RCC (ESC RCC) [32–34]. However, the presence of the blue granules/basophilic stippling may not be a specific morphologic feature as they have been described to be present in other TSC/MTOR/folliculin/TFE3/TFEB pathway mutated renal tumors apart from ESC RCC [35, 36].

While the morphologic features of this purely solid MED15::TFE3 RCC are highly similar to those of CCRCC, its IHC profile could be helpful in distinguishing it from CCRCC, although some caveats exist. Similar to the conventional MED15::TFE3 RCCs that are extensively cystic, the purely solid MED15::TFE3 RCC was positive for TFE3, and mostly negative for CAIX, which would be highly unusual for CCRCC. However, it did show focal strong box-like membranous positivity for CAIX, primarily in the areas of fragmentation/degeneration, and one should be mindful to refrain from misinterpreting this focal membranous positivity as evidence supporting the diagnosis of CCRCC as CCRCC usually has diffuse box-like membranous staining, not focal. Additionally, as the CD10 positivity was seen in this purely solid MED15::TFE3 RCC, as it is often seen in CCRCC, CD10 positivity should be interpreted with caution, especially in the setting where diffuse membranous CAIX positivity is not seen. Interestingly, this purely solid MED15::TFE3 RCC was negative for Melan-A, and one should be mindful that TFE3-rearranged RCCs can be negative for melanocytic markers and should not hastily exclude TFE3-rearranged RCC based on the melanocytic marker negativity. Conversely, TFE3 positivity, while it is a helpful clue towards the diagnosis of TFE3-rearrnaged RCC, can have false positives in various renal tumors such as FH-deficient RCC [37], ALK-rearranged RCC [38], and FLCN-mutant renal epithelial tumors [39], and should be interpreted with caution. In challenging cases where the distinction between CCRCC and purely solid MED15::TFE3 RCC is difficult, molecular tests could aid in definitive classification, as CCRCC has its characteristic VHL mutation and/or loss of chromosome 3p and no TFE3 rearrangement, and vice versa for the MED15::TFE3 RCC. As CCRCC and the current case of purely solid MED15::TFE3 RCC have significant morphologic overlap, one’s threshold for ordering ancillary IHC and/or molecular tests should be low, especially when it can lead to different clinical managements. Basic IHC panel of CAIX and TFE3 could be very useful in this setting, and NGS and/or TFE3 fluorescent in situ hybridization (FISH) could also aid in definitive classification if necessary.

Case 6 in the current study also showed an unconventional morphology for a MED15::TFE3 RCC as it was predominantly solid and tubulopapillary with only minor cystic components. Morphologically, it had some features that are reminiscent of (formerly) papillary RCC (PRCC), type 1, although the presence of psammomatous calcifications and the tumor cells with clear cytoplasm, especially in the minor cystic component, should alert one to promptly order additional work up. TFE3 and CK7 can be helpful in this diagnostic scenario, as CK7 is negative in MED15::TFE3 RCC and usually positive in (formerly) PRCC, type 1, and TFE3 is positive in MED15::TFE3 RCC and negative in (formerly) PRCC, type 1, although the same caveat exists for the interpretation of TFE3 as described above. It must be noted that CD10 and P504S should be interpreted with caution in this scenario, as Case 6 showed apical CD10 staining pattern and P504S positivity, similar to the patterns observed in PRCC. Interestingly, Case 6 was negative for Melan A in both cystic and tubulopapillary components similar to the purely solid MED15::TFE3 RCC (Case 5), similar to Case 5.

To this date, there is no report of patients with MED15::TFE3 RCC dying from the disease. There was only one reported case of metastasis, which was from the cohort by Wang et al. [8], and the patient is still alive after 15 years. Data to this date suggest that MED15::TFE3 RCCs are mostly indolent-behaving compared to the most TFE3-rearranged RCCs, the prognosis of which could vary depending on the fusion partner gene [1, 6, 40, 41]. Given the indolent nature of the tumor, including the ones with solid architecture, distinguishing them from CCRCC, which has more aggressive behavior, could be clinically important as the accurate distinction may affect subsequent clinical follow up and work up.

Additionally, some interesting molecular-phenotypic correlations were observed between the conventional extensively cystic MED15::TFE3 RCCs and those with unusual morphologic features (Cases 5—6). Conventional MED15::TFE3 RCCs that are extensively cystic with Melan-A positivity uniformly have fusion transcripts that show a connection to exon 6 of TFE3, although the connection point of MED15 can vary. However, the non-cystic MED15::TFE3 RCCs with Melan-A negativity (Cases 5—6) both have fusion transcripts that show a connection to different exons other than the exon 6, with Case 5 with a transcript showing a connection to exon 7 of TFE3 and Case 6 with a transcript showing a connection to exon 4 of TFE3. Additionally, the purely solid MED15::TFE3 RCC (Case 5) is unique compared to all other MED15-TFE3 RCCs as it has two distinct MED15::TFE3 fusion transcripts with one of them having an intron of MED15 as a connection point. This is the only reported case of MED15::TFE3 RCCs that has two distinct fusion transcripts and have an intron as a connection point and also happens to be the only reported case of purely solid MED15::TFE3 RCCs. Although it is unclear what the functional impact of these various fusion transcripts is, these findings imply that the connection points of the fusion transcripts may have impact on tumor phenotypes even within the TFE3 fusion with the same partner gene of MED15. Although this is an extrapolation, these findings could also imply that the property of the fusion transcripts itself may contribute to the heterogeneity of tumor phenotypes observed in tumors with specific driver pathogenic fusion transcripts with the same partner gene. However, further studies with additional cases are required to validate this finding.

To conclude, this study reports two solid MED15::TFE3 RCCs with morphologic, immunohistochemical, and molecular features that are different from their cystic counterpart. In particular, the purely solid MED15::TFE3 RCC in this case morphologically mimic CCRCC and it would be important for pathologists to recognize when to order ancillary studies to confirm or exclude the diagnosis as the accurate distinction may have clinical consequences. Phenotypic variation within the MED15::TFE3 RCCs may be due to the innate property of the fusion transcripts, although additional studies are required to validate this finding.

Authors’ contributions

Tatjana Antic and Jung Woo Kwon contributed to the study conception and design. Material preparation, data collection and analysis were performed by all authors (Sarah Mae Lammert, Hayley Zullow, Peng Wang, Melissa Y. Tjota, Tatjana Antic and Jung Woo Kwon). The first draft of the manuscript was written by Jung Woo Kwon. All authors (Sarah Mae Lammert, Hayley Zullow, Peng Wang, Melissa Y. Tjota, Tatjana Antic and Jung Woo Kwon) commented on previous versions of the manuscript. All authors (Sarah Mae Lammert, Hayley Zullow, Peng Wang, Melissa Y. Tjota, Tatjana Antic and Jung Woo Kwon) read and approved the final manuscript.

Declarations

Research involving Human Participants and/or Animals

Yes (human participants).

Ethical approval

Approved by the University of Chicago Institutional Review Board.

Informed consent

Waived by the University of Chicago Institutional Review Board.

Ethical treatment of patients

Not applicable as this is a retrospective study.

Conflicts of interests

All authors have no interests to declare.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

1.WHO Classification of Tumours, 5^th Edition (2022), Volume 8: Urinary and Male Genital Tumours. [DOI] [PubMed]
2.Argani P, Zhong M, Reuter VE et al (2016) TFE3-fusion variant analysis defines specific clinicopathologic associations among Xp11 translocation cancers. Am J Surg Pathol 40(6):723–737. 10.1097/PAS.0000000000000631 [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Huang W, Goldfischer M, Babayeva S et al (2015) Identification of a novel PARP14-TFE3 gene fusion from 10-year-old FFPE tissue by RNA-seq. Genes Chromosomes Cancer 54(8):500–505. 10.1002/gcc.22261 [DOI] [PubMed] [Google Scholar]
4.Fukuda H, Kato I, Furuya M et al (2019) A novel partner of TFE3 in the Xp11 translocation renal cell carcinoma: clinicopathological analyses and detection of EWSR1-TFE3 fusion. Virchows Arch 474(3):389–393. 10.1007/s00428-018-2509-8 [DOI] [PubMed] [Google Scholar]
5.Argani P, Antonescu CR, Illei PB et al (2001) Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol 159(1):179–192. 10.1016/S0002-9440(10)61684-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Tretiakova MS (2022) Chameleon TFE3-translocation RCC and how gene partners can change morphology: accurate diagnosis using contemporary modalities. Adv Anat Pathol 29(3):131–140. 10.1097/PAP.0000000000000332 [DOI] [PubMed] [Google Scholar]
7.Kuentz MA, Blons H, Gimenez-Roqueplo AP et al (2023) A novel VCP::TFE3 gene fusion resulting from t(X;9)(p11.23;p13.3) chromosome translocation in TFE3 rearranged renal cancer cell carcinoma. Genes Chromosomes Cancer 62(6):361–366. 10.1002/gcc.23127 [DOI] [PubMed] [Google Scholar]
8.Wang XT, Xia QY, Ye SB et al (2018) RNA sequencing of Xp11 translocation-associated cancers reveals novel gene fusions and distinctive clinicopathologic correlations. Mod Pathol 31(9):1346–1360. 10.1038/s41379-018-0051-5 [DOI] [PubMed] [Google Scholar]
9.Pei J, Cooper H, Flieder DB et al (2019) NEAT1-TFE3 and KAT6A-TFE3 renal cell carcinomas, new members of MiT family translocation renal cell carcinoma. Mod Pathol 32(5):710–716. 10.1038/s41379-018-0191-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Classe M, Malouf GG, Su X et al (2017) Incidence, clinicopathological features and fusion transcript landscape of translocation renal cell carcinomas. Histopathology 70(7):1089–1097. 10.1111/his.13167 [DOI] [PubMed] [Google Scholar]
11.Argani P, Matoso A, Baraban EG, Epstein JI, Antonescu CR (2023) MED15::TFE3 renal cell carcinomas: report of two new cases and review of the literature confirming nearly universal multilocular cystic morphology. Int J Surg Pathol 31(4):409–414. 10.1177/10668969221143455 [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Ye H, Qin S, Li N, Lin M, Xu Y, Li X (2019) A rare partner of TFE3 in the Xp11 translocation renal cell carcinoma: clinicopathological analyses and detection of MED15-TFE3 fusion. BioMed Res Int 2019:5974089. 10.1155/2019/5974089 [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Song Y, Yin X, Xia Q et al (2021) 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. J Clin Pathol 74(3):171–176. 10.1136/jclinpath-2020-206681 [DOI] [PubMed] [Google Scholar]
14.Doytcheva K, Gallan AJ, Wang P, Wanjari P, Segal J, Antic T (2023) Cystic MED15::TFE3 translocation renal cell carcinoma: histologic mimicker of multilocular cystic renal neoplasm of low malignant potential with review of the literature. Hum Pathol 136:25–33. 10.1016/j.humpath.2023.03.008 [DOI] [PubMed] [Google Scholar]
15.Mladenovic A, Harik LR, Deeb KK, Genega EM, Saeed F, Gandhi JS (2025) TFE3/TFEB altered renal cell carcinomas in end-stage renal disease setting: a single institution clinicopathological study of 4 cases. Hum Pathol 158:105783. 10.1016/j.humpath.2025.105783 [DOI] [PubMed] [Google Scholar]
16.Deng Z, Xu Y, Duan E et al (2025) MED15-TFE3 rearranged renal cell carcinoma: a subtype of TFE3-rearranged renal cell carcinoma with unique clinicopathologic features and better prognosis. World J Surg Oncol 23(1):385. 10.1186/s12957-025-04048-x [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Yin X, Hu X, Xu J, Xiong D, Zhao M (2024) MED15::TFE3 fusion renal cell carcinoma with extensive cystic change: a clinicopathologic and molecular genetic study of 2 cases, with an emphasis on differential diagnosis. Am J Clin Pathol 162(1):86–94. 10.1093/ajcp/aqae011 [DOI] [PubMed] [Google Scholar]
18.Harada S, Caliò A, Janowski KM et al (2021) Diagnostic utility of one-stop fusion gene panel to detect TFE3/TFEB gene rearrangement and amplification in renal cell carcinomas. Mod Pathol 34(11):2055–2063. 10.1038/s41379-021-00858-y [DOI] [PubMed] [Google Scholar]
19.Cai Q, Gagan J, Koduru P et al (2024) Multicystic clear cell renal tumors with low-grade nuclear features: time to include TFE3 translocation-associated carcinomas. Adv Anat Pathol 31(1):34–42. 10.1097/PAP.0000000000000420 [DOI] [PubMed] [Google Scholar]
20.Sun G, Chen J, Liang J et al (2021) Integrated exome and RNA sequencing of TFE3-translocation renal cell carcinoma. Nat Commun 12(1):5262. 10.1038/s41467-021-25618-z [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Achom M, Sadagopan A, Bao C et al (2024) A genetic basis for sex differences in Xp11 translocation renal cell carcinoma. Cell 187(20):5735-5752.e25. 10.1016/j.cell.2024.07.038 [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Dobin A, Davis CA, Schlesinger F et al (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29(1):15–21. 10.1093/bioinformatics/bts635 [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Kadri S, Long BC, Mujacic I et al (2017) Clinical validation of a next-generation sequencing genomic oncology panel via cross-platform benchmarking against established amplicon sequencing assays. J Mol Diagn 19(1):43–56. 10.1016/j.jmoldx.2016.07.012 [DOI] [PubMed] [Google Scholar]
24.Sun W, Yue J, Fan L (2024) Clear cell renal cell carcinoma with syncytial giant cells: not that rare. Pathol Res Pract 253:155043. 10.1016/j.prp.2023.155043 [DOI] [PubMed] [Google Scholar]
25.Shen R, Wen P (2004) Clear cell renal cell carcinoma with syncytial giant cells: a case report and review of the literature. Arch Pathol Lab Med 128(12):1435–1438. 10.5858/2004-128-1435-CCRCCW [DOI] [PubMed] [Google Scholar]
26.Lloreta J, Bielsa O, Munné A et al (2002) Renal cell carcinoma with syncytial giant cell component. Virchows Arch 440(3):330–333. 10.1007/s004280100522 [DOI] [PubMed] [Google Scholar]
27.Berzal Cantalejo F, Sabater Marco V, Alonso Hernández S, Jiménez Peña R, Martorell Cebollada MA (2004) Syncytial giant cell component. Review of 55 renal cell carcinomas. Histol Histopathol 19(1):113–118. 10.14670/HH-19.113 [DOI] [PubMed] [Google Scholar]
28.Sangoi AR, Al-Obaidy KI, Cheng L et al (2023) Clear cell renal cell carcinoma with focal psammomatous calcifications: a rare occurrence mimicking translocation carcinoma. Histopathology 82(5):684–690. 10.1111/his.14854 [DOI] [PubMed] [Google Scholar]
29.Nova-Camacho LM, Sangoi AR (2024) Clear cell renal cell carcinoma with syncytial-type multinucleated giant tumor cells: a clinicopathologic study of 14 cases. Int J Surg Pathol 32(4):731–737. 10.1177/10668969231189798 [DOI] [PubMed] [Google Scholar]
30.Williamson SR, Kum JB, Goheen MP, Cheng L, Grignon DJ, Idrees MT (2014) Clear cell renal cell carcinoma with a syncytial-type multinucleated giant tumor cell component: implications for differential diagnosis. Hum Pathol 45(4):735–744. 10.1016/j.humpath.2013.10.033 [DOI] [PubMed] [Google Scholar]
31.Gallan AJ, Parilla M, Segal J, Ritterhouse L, Antic T (2021) BAP1-Mutated clear cell renal cell carcinoma. Am J Clin Pathol 155(5):718–728. 10.1093/ajcp/aqaa176 [DOI] [PubMed] [Google Scholar]
32.Tjota M, Chen H, Parilla M, Wanjari P, Segal J, Antic T (2020) Eosinophilic renal cell tumors with a TSC and MTOR gene mutations are morphologically and immunohistochemically heterogenous: clinicopathologic and molecular study. Am J Surg Pathol 44(7):943–954. 10.1097/PAS.0000000000001457 [DOI] [PubMed] [Google Scholar]
33.Trpkov K, Hes O, Bonert M et al (2016) Eosinophilic, solid, and cystic renal cell carcinoma: clinicopathologic study of 16 unique, sporadic neoplasms occurring in women. Am J Surg Pathol 40(1):60–71. 10.1097/PAS.0000000000000508 [DOI] [PubMed] [Google Scholar]
34.Palsgrove DN, Li Y, Pratilas CA et al (2018) Eosinophilic solid and cystic (ESC) renal cell carcinomas harbor TSC mutations: molecular analysis supports an expanding clinicopathologic spectrum. Am J Surg Pathol 42(9):1166–1181. 10.1097/PAS.0000000000001111 [DOI] [PMC free article] [PubMed] [Google Scholar]
35.Kwon JW, Tjota MY, Antic T. 2025 MTOR-mutated eosinophilic renal cell carcinomas with loss of chromosome 1 and high metastatic potential: further expanding the spectrum of TSC/mTOR pathway mutated renal tumors. Virchows Arch. 10.1007/s00428-025-04363-4 [DOI] [PMC free article] [PubMed]
36.Argani P (2026) MiT family translocation carcinomas of the kidney and related entities. Histopathology 88(1):193–213. 10.1111/his.15560 [DOI] [PubMed] [Google Scholar]
37.Kuroda N, Tsutsui M, Iguchi M et al (2020) Fumarate hydratase-deficient renal cell carcinoma: a clinicopathological study of seven cases including hereditary and sporadic forms. Ann Diagn Pathol 49:151599. 10.1016/j.anndiagpath.2020.151599 [DOI] [PubMed] [Google Scholar]
38.Zhao M, Yin X, Yang X et al (2024) ALK-rearranged renal cell carcinoma: a multi-institutional study of 9 cases with expanding the morphologic and molecular genetic spectrum. Mod Pathol 37(8):100536. 10.1016/j.modpat.2024.100536 [DOI] [PubMed] [Google Scholar]
39.Argani P, Baraban E, Yaskiv O et al (2025) Clinically sporadic Folliculin -mutated renal epithelial neoplasms represent a mixture of true somatic Folliculin -mutated and occult Birt-Hogg-Dubé syndrome-associated cases : morphologic and molecular overlap with TSC/MTOR -mutated eosinophilic renal neoplasms and MiT family translocation renal cell carcinoma. Am J Surg Pathol 49(9):859–872. 10.1097/PAS.0000000000002413 [DOI] [PubMed] [Google Scholar]
40.Ge Y, Lin X, Zhang Q et al (2021) Xp11.2 translocation renal cell carcinoma with TFE3 rearrangement: distinct morphological features and prognosis with different fusion partners. Front Oncol 11:784993. 10.3389/fonc.2021.784993 [DOI] [PMC free article] [PubMed] [Google Scholar]
41.Ellis CL, Eble JN, Subhawong AP et al (2014) Clinical heterogeneity of Xp11 translocation renal cell carcinoma: impact of fusion subtype, age, and stage. Mod Pathol 27(6):875–886. 10.1038/modpathol.2013.208 [DOI] [PubMed] [Google Scholar]

PERMALINK

Comprehensive analysis of six MED15::TFE3 renal cell carcinomas including two novel solid MED15::TFE3 renal cell carcinomas, highlighting their morphologic, immunohistochemical and molecular differences from their cystic counterparts

Jung Woo Kwon

Sarah Mae Lammert

Hayley Zullow

Peng Wang

Melissa Yuwono Tjota

Tatjana Antic