Interesting cases

1. b
2. c

1. TFE3 IHC and TFE3 FISH
2. TFE3-rearranged renal cell carcinoma

The core biopsy showed lesional tissue with tubulopapillary architecture (Fig 1). The cells showed abundant clear to eosinophilic, focally flocculent cytoplasm and low grade nuclei with inconspicuous nucleoli (Fig 2). The nuclei generally showed reverse polarity (Fig 3) and striking subnuclear vacuoles were seen (Fig 4). No psammoma bodies were identified. There was no melanin pigment. There was no rhabdoid or sarcomatoid differentiation and no necrosis was seen. The cells were diffusely positive for PAX8 and Alpha methyacyl CoA racemase (AMACR). Carbonic anhydrase IX (CAIX) lacked membranous expression though it showed patchy nonspecific perinuclear dot-like staining pattern. Keratin 7 (KRT 7), melan A, HMB45, cathepsin K and ALK (D5F3) were negative (Fig 5). Succinate dehydrogenase B (SDHB) showed retained (intact) granular cytoplasmic expression. TFE3 immunohistochemistry showed strong and diffuse nuclear expression (Fig 6). TFE3 FISH demonstrated a signal pattern consistent with a TFE3 rearrangement (split of red and green signals in 80% of the tumour cells) (Fig 6). A diagnosis of TFE3-rearranged RCC (TFE3-RCC) was rendered. The patient then underwent robot-assisted resection of the mass. Macroscopically the lesion was circumscribed unencapsulated with a yellow tan and haemorrhagic cut surface, 42 x 22 x 20 mm (Fig 7). Microscopically the lesion had similar features similar to those identified in the biopsy. Targeted next generation sequencing (NGS) using the TruSight RNA Fusion Panel (Illumina) was performed on the resection specimen and detected a SFPQ::TFE3 rearrangement.
TFE3-RCCs harbour gene fusions involving TFE3 with one of many different partner genes. They account for approximately 40% of paediatric RCCs and 1.6-4% of adult RCCs [1]. Classically they exhibit heterogeneous morphology with papillary architecture, clear to eosinophilic cytoplasm and psammoma bodies. The clinicopathological and microscopic features, however, overlap with other RCC subtypes and vary according to the type of partner gene involved [2].
In this tumour the negative CAIX excluded clear cell RCC. Lack of KRT 7 expression rendered papillary renal cell carcinoma unlikely. Though the tubulopapillary architecture, subnuclear vacuoles and apical nuclei suggested clear cell papillary renal cell tumour, the dual CAIX/KRT7 negative immunophenotype excluded this possibility. The presence of subnuclear vacuoles and apical nuclei are features typical of SFPQ::TFE3 RCC [3] that was confirmed by NGS in this tumour. SFPQ::TFE3 RCCs can also show clusters of small cells with pseudorosette formation mimicking TFEB RCC, as well as sarcomatoid morphology [4]. Nuclear palisading with subnuclear vacuoles are also typical of NONO::TFE3 RCC, though TFE3 FISH may give a false negative result due to paracentric inversions involving Xp11 [1]. SFPQ::TFE3 fusion can also occur in perivascular epithelioid cell tumours (PEComas) and melanotic Xp11 translocation renal cell cancers. Both these tumours demonstrate solid nested architecture and epithelioid cells with clear to eosinophilic cytoplasm with melanin pigment identifiable in the latter. Both are PAX8 negative and cathepsin K positive [3].
The survival of patients with TFE3-RCCs is similar to that of patients with clear cell RCCs and significantly worse than that of patients with papillary RCCs [1]. Wang et al. examined 5 SFPQ::TFE3 RCCs and reviewed the literature. Available follow-up data on 18 SFPQ::TFE3 RCCs (2 to 125, mean 44.7, median 45 months) showed that 16 were alive with no evidence of disease, one had a recurrence after 3 years and one died of metastatic disease [4].

1. Amin MB, Berney DM, Compérat, EM, et al. Tumours of the Kidney. In: WHO Classification of Tumours Editorial Board. Urinary and male genital tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2022 [cited 2023/10/10]. (WHO classification of tumours series, 5th ed.; vol. 8). Available from: https://tumourclassification.iarc.who.int/chapters/36.
2. Kmeid M, Akgul M. TFE3 Rearrangement and Expression in Renal Cell Carcinoma. Int J Surg Pathol. 2023 Aug;31(5):509-520.
3. Argani P, Zhong M, Reuter VE, Fallon JT, Epstein JI, Netto GJ, Antonescu CR. TFE3-Fusion Variant Analysis Defines Specific Clinicopathologic Associations Among Xp11 Translocation Cancers. Am J Surg Pathol. 2016 Jun;40(6):723-737.
4. Wang XT, Xia QY, Ni H, Ye SB, Li R, Wang X, Shi SS, Zhou XJ, Rao Q. SFPQ/PSF-TFE3 renal cell carcinoma: a clinicopathologic study emphasizing extended morphology and reviewing the differences between SFPQ-TFE3 RCC and the corresponding mesenchymal neoplasm despite an identical gene fusion. Hum Pathol. 2017 May;63:190-200.

Laurence A Galea (1), Christopher Joy (2), Charles Han (3), Benhur Amanuel (4)
1. Department of Anatomical Pathology, Melbourne Pathology, Sonic Healthcare, Victoria, Australia
2. Department of Cytogenetics, Sullivan Nicolaides Pathology, Sonic Healthcare, Queensland, Australia.
3. Department of Urology, Epworth Eastern Hospital, Victoria, Australia.
4. Anatomical Pathology, PathWest Laboratory Medicine, Western Australia, Australia.

Twitter handles: @DrLaurenceGalea

Kidney

TFE3-rearranged renal cell carcinoma, TFE3, SFPQ::TFE3