A potential conundrum in dermatopathology: molecularly confirmed superficial ossifying fibromyxoid tumors with unusual histomorphologic findings and a novel fusion.

Ossifying fibromyxoid tumor (OFMT) is a rare soft tissue neoplasm of uncertain histogenesis, primarily arising in subcutaneous tissues of the extremities, head and neck, or trunk. Most cases present as well-circumscribed masses with a characteristic morphologic appearance, comprising cytologically bland ovoid cells with fibromyxoid stroma, a peripheral rim of metaplastic bone, and lobulated architecture. Nevertheless, tumors displaying unusual morphologic characteristics pose significant diagnostic challenges, requiring the detection of a pathogenic fusion for a definitive diagnosis. The majority of OFMTs exhibits PHF1 gene rearrangements. Herein, we present six cases of molecularly confirmed OFMTs with uncommon histomorphologic features, including the absence of myxoid stroma, extensive chondroid differentiation, prominent clear cell morphology, collagen entrapment, interdigitating fibrocollagenous and fibromyxoid stromal elements, and conspicuous red blood cell extravasation. One case harbored a novel fusion (EPC1::SUZ12). This study emphasizes the broad range of morphologic manifestations that can be encountered in OFMT and the crucial role of molecular testing in establishing a conclusive diagnosis in such cases.

TFE3-rearranged RCC with osseous metaplasia found on bone mass densitometry.

Introduction and importance: Renal cell carcinoma (RCC) is the most common primary renal malignancy in patients between the ages of 50 and 70. A rare described variant of RCC is transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3) rearranged RCC. Osseous metaplasia, which refers to the occurrence of normal bone tissue in soft tissue, has been observed in all subtypes of renal cell carcinoma (RCC); however, only three previous case reports have documented the occurrence of osseous metaplasia in TFE3-rearranged RCC. Case presentation: We present a case of a 65-year-old woman presenting with an incidentally discovered calcified Bi-lobed renal mass detected on bone densitometry composed of a calcified thick-walled cyst measuring 7×6.5×6.5 cm showing intraluminal densities and heterogeneous content, and a lobulated partially exophytic renal mass measuring 4.5×5.5×4.5 cm. The patient underwent robotic-assisted radical nephrectomy confirming the diagnosis of RCC with osseous metaplasia extending into the pelvic calyces and renal sinus fat implicating a pathological stage of T3a. Clinical discussion: TFE3-rearranged RCCs represent a rare sub-classification in adult RCCs. It may be associated with unfavorable prognosis and aggressive patterns of disease in the presence of osseous metaplasia. Conclusion: This is the first case in the literature of TFE3-rearranged RCC with osseous metaplasia on bone mass densitometry scan and the fourth case of TFE3-rearranged RCC with osseous metaplasia. The patient is to be treated as a high-risk patient and to be monitored closely for recurrence of malignancy, as indicated in the EAU guidelines.

Malignant Perivascular epithelioid cell tumour of the uterus without TFE3 gene rearrangement: a case report.

BACKGROUND: Perivascular epithelioid cell tumours (PEComas) are soft tissue tumours. These neoplasms belong to the family of mesenchymal tumours, which include angiomyolipomas, clear-cell sugar tumours of the lung, and PEComas not otherwise specified (NOS). The probability of a perivascular epithelioid cell tumour (PEComa) occurring in the uterus is low, and the incidence, diagnosis, treatment, and outcomes of such tumours are still unclear. CASE PRESENTATION: A 51-year-old woman presented a 4-year history of natural menopause. An intrauterine mass was detected via ultrasound examination; the mass showed a tendency to increase but caused no symptoms. The levels of tumour markers were within the normal range. Pathological analysis of the curettage revealed perivascular epithelioid differentiation of the endometrial tumour. Consequently, a laparoscopic total hysterectomy with bilateral adnexectomy was performed. No distant metastasis was detected via whole-body positron emission computed tomography (PETCT) after the operation. Fluorescence in situ hybridization (FISH) revealed no TFE3 gene rearrangement. Next-generation sequencing of bone and soft tissue revealed negative TSC1/2 and TP53 expression. No recurrence or metastasis was observed during the 18-month follow-up period. CONCLUSION: PEComa of the gynecologic tract is a rare and challenging entity. Diffuse HMB-45 expression, TSC alterations and TFE3 rearrangement are characteristic of uterine PEComas. Surgical resection is the first choice. Genetic testing is helpful for determining the nature of the mass and for choosing targeted therapy. Further research is needed to establish treatment protocols.

Inflammatory spindle cell PEComa of the lung with YAP1::TFE3 fusion: a report of two cases and a potential relationship with clear cell stromal tumour.

AIMS: The PEComa family of tumours is defined by spindle/epithelioid cells with myomelanocytic differentiation. A small subset harbours TFE3 fusion; however, YAP1::TEE3 has not been reported. Clear cell stromal tumour of the lung (CCST-L) is an emerging entity characterized by spindle to epithelioid cells with focal cytoplasmic clearing, inflammatory infiltrates, no myomelanocytic differentiation, and YAP1::TFE3 fusion. Herein, we report two cases of lung tumours with myomelanocytic differentiation that showed inflammatory spindle cell histology, focal epithelioid clear cells, as well as YAP1::TFE3 fusion. METHODS AND RESULTS: The patients were both men, aged 61 and 68 years. The tumours in both cases presented as well-circumscribed solid masses involving the lung hilum. After lobectomy, no recurrence was observed at 7 and 32 months. Both tumours shared storiform to short fascicular growth of long spindle cells, with a minor component of epithelioid cells showing clear cytoplasm in the background of substantial intratumoral chronic inflammation and dilated blood vessels. One tumour showed focal melanin deposition. Both tumours were immunohistochemically positive for HMB45, Melan A, and h-caldesmon. Fluorescence in situ hybridization assays indicated the presence of YAP1::TFE3 fusions, which was confirmed by RNA sequencing in one case tested, and by immunohistochemical TFE3 expression and loss of YAP1 C-terminus staining. CONCLUSION: We present two cases of inflammatory spindle to epithelioid cell tumours of the lungs with myomelanocytic differentiation and YAP1::TFE3 fusion. This unique morphology and gene fusion suggest that these tumours may constitute a distinct subset of lung PEComa. Furthermore, morphological and molecular overlap with CCST-L gives rise to a hypothesis of a potential inherent relationship between PEComa and CCST-L.

Secondary TFE3-Rearranged Renal Cell Carcinoma in a Chinese Girl Treated for Wilms Tumor: Case Report and Literature Review.

Background: With the development of modern medicine and the application of multimodal treatment strategies, the survival rate after childhood malignant tumors as well as the incidence of Secondary malignant neoplasm (SMN) have increased. Case report: Patient is a Chinese girl. Initially diagnosed with Wilms tumor affecting her left kidney at the age of 6, she was later found to have TFE3-rearranged renal cell carcinoma (rRCC) affecting her right kidney at the age of 12. Employing NGS technology on specimens obtained from the TFE3-rRCC, we uncovered a significant somatic mutation within PRSS8 gene. This discovery sheds new light on the intricate genetic landscape underlying her condition, paving the way for further exploration and personalized treatment strategies. Conclusion: We consider that the etiology of SMN may be the result of chemoradiotherapy.

A Novel TEK::GAB2 Gene Fusion in Pediatric Angiosarcoma of Pelvic soft Tissue: A Case Report and Literature Review.

Pediatric angiosarcoma of soft tissue, an extremely rare entity, remains poorly understood from a genetic standpoint. Herein, we present the case of a previously healthy 17-year-old girl with acute left hip pain. Subsequent magnetic resonance imaging revealed a 21.8 cm left pelvic sidewall mass with heterogeneous enhancement and multiple lung nodules. Biopsy of the tumor showed an infiltrative, hemorrhagic neoplasm composed primarily of atypical spindle to epithelioid cells. Focal vasoformative architecture was appreciated. Immunohistochemically, the tumor cells were strongly positive for CD31, ERG, and FLI-1, supporting the diagnosis of angiosarcoma. Genetic analysis identified a novel TEK::GAB2 gene fusion. TEK belongs to the angiopoietin receptor family, and its fusion with GAB2 is predicted to mediate tumorigenesis. This report expands the current knowledge on the spectrum of gene rearrangements of angiosarcoma.

PHF1::TFE3-positive fibromyxoid sarcoma? Report of 2 cases and review of 13 cases of PHF1::TFE3-positive ossifying fibromyxoid tumor in the literature.

OBJECTIVES: Ossifying fibromyxoid tumor (OFMT) is a rare soft tissue neoplasm of uncertain histogenesis. Most OFMTs have benign behavior, and many harbor gene fusions involving the PHD finger protein 1 (PHF1), such as EP400::PHF1, MEAF6::PHF1, EPC1::PHF1, and PHF1::TFE3. The PHF1::TFE3 fusion is unique because PHF1 is at 5' instead of residing at 3' in the other fusions. In this study, we describe 2 cases of OFMT harboring PHF1::TFE3 fusions and review 13 published cases. METHODS: Two cases of PHF1::TFE3-positive OFMT were investigated using RNA Next-Generation Sequencing and immunohistochemistry. RESULTS: Most (12/15) of the PHF1::TFE3 OFMTs we studied were located at proximal and distal extremities, with a multinodular growth pattern. Only 1 case (1/10) had a shell of bone at the periphery. Areas morphologically similar to sclerosing epithelioid fibrosarcoma or low-grade fibromyxoid sarcoma were found in 8 of 12 (66.7%) cases. Eleven cases (11/15 [73.3%]) were regarded as malignant based on more than 2/50 high-power field mitotic figures, increased cellularity, or the presence of necrosis. Among the 9 cases with follow-up data, 2 patients died of disease (with metastases), 1 patient is alive with metastases, and 1 patient had multiple local recurrences. CONCLUSIONS: Because PHF1 is located at 3' in all the PHF1 fusions in OFMTs except PHF1::TFE3, the different driver molecular alterations suggest that OFMTs with 3'-PHF1 fusions and OFMTs with PHF1::TFE3 are different tumors. Immunohistochemistry confirmed TFE3 expression in all PHF1::TFE3 OFMTs. Because PHF1::TFE3-positive OFMTs have increased mitotic figures and tumor cellularity, with a high rate of metastasis, using the name PHF1::TFE3 positive fibromyxoid sarcoma may be appropriate.

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.

The Clinicopathological Characteristics and Prognosis of 55 Patients With TFE3-Rearranged Renal Cell Carcinomas.

OBJECTIVE: To explore the clinicopathological features and prognosis of TFE3-rearranged renal cell carcinomas (TFE3-rRCC). METHODS: In this retrospective observational study, the data of patients with TFE3-rRCC admitted to Xijing Hospital from January 2010 to October 2023 were collected, encompassing the general information, pathological diagnosis, immunohistochemistry, and the results of FISH detection. The treatment information and survival data of the patients were recorded during the follow-up. RESULTS: A total of 55 patients with TFE3-rRCC were enrolled, among whom 25 were males and 30 were females. TFE3 FISH assay suggested the disruption of the TFE3 gene. Fifty-four patients underwent surgical resection of kidney lesions, while 1 patient did not. By the end of follow-up in December 2023, 3 patients were lost to follow-up, 28 patients remained alive, and 24 patients had died. Among the 52 patients followed up, 31 developed metastases, involving lymph nodes, liver, bone, lung, peritoneum, pleura, adrenal gland, and brain. The 1-year and 5-year survival rates of the patients were 84.6% and 50.6%, respectively. In this study, there were 31 patients with TFE3-rRCC recurrence or metastasis. Median PFS was 7 and 13 months in the VEGFR-TKI and VEGFR-TKI+ ICI groups, respectively. The median OS was 12 months in the VEGFR-TKI treatment group. The median OS data of VEGFR-TKI+ ICI group has not been reached. The ORR and DCR was 25%, 66.7% in the VEGFR-TKI group. The ORR and DCR was 33.3%, 77.8% in the VEGFR-TKI+ ICI group. CONCLUSION: TFE3-rRCC is a rare subtype of malignant renal tumor. The diagnosis mainly relies on pathological morphology, immunohistochemistry, and the detection of TFE3 gene disruption by FISH. In terms of treatment, surgery is the primary approach, and lymph nodes, liver, and bone are the main metastatic sites. VEGFR-TKI+ICI treatment might be an option of recurrent or metastatic TFE3-rRCC.

Approach to Diagnosis of TFE3-rearranged Renal Cell Carcinoma in a Limited Resource Setting: A Case Report.

This report recounts the diagnostic workup of a pediatric female who presented with hematuria secondary to a large renal mass visualized on abdominal imaging. Histologic assessment and subsequent immunohistochemistry studies were performed. Intense, unequivocal immunohistochemical expression of TFE3 and alpha-methylacyl-CoA-racemase with corresponding negativity for carbonic anhydrase IX, along with highly distinctive clinical, radiologic, gross, and microscopic findings confirmed the diagnosis of a renal cell carcinoma with TFE3 gene rearrangement - the first ever reported case in the Philippines. This case highlights the vital role and significant diagnostic impact of reliable, affordable and accessible immunohistochemistry studies in low-resource settings where molecular modalities for evaluating rare diseases are largely unavailable. Recognition of distinctive morphologic, immunohistochemical, and cytogenetic features in childhood and adolescent renal malignancies allows for the timely institution of therapeutic interventions for this aggressive entity.

A case of NONO::TFE3 cutaneous epithelioid and spindle cell tumor with local recurrence after complete excision.

Mesenchymal tumors may display morphologic and immunohistochemical overlap with melanocytic tumors, presenting a pitfall for misdiagnosis. We report a 62-year-old woman who presented with a recurrent dermal and subcutaneous tumor over the Achilles tendon 15 years following complete excision. Both the primary and the recurrent tumors were characterized by nests and sheets of epithelioid and spindle cells with eosinophilic cytoplasm and uniform ovoid nuclei. The tumor was positive for S100, SOX10, HMB45, cathepsin K, and p63 (weak), while negative for Melan-A, MiTF, smooth muscle actin, and desmin. Gene fusion analysis of the recurrent tumor revealed a NONO::TFE3 fusion which has been recently reported in two similar cutaneous cases. Our case highlights the potential of a NONO::TFE3 cutaneous epithelioid and spindle cell tumor to recur after a prolonged disease-free interval without evidence of high-grade transformation or distant metastasis. Our findings support its classification as a cutaneous mesenchymal neoplasm of intermediate malignancy.

Four years of natural progressive course: A rare case report of juvenile Xp11.2 translocations renal cell carcinoma with TFE3 gene fusion.

Background: Renal cell carcinoma (RCC) with TFE3 gene fusion caused by Xp11.2 translocations is a rare RCC subtype. This tumor is typically seen in children, comprising 20‒40% of overall RCC cases compared to 1‒1.6% observed in adults. Xp11.2 RCC is associated with a poor prognosis due to both the progression of local lesions and early distant and lymphatic metastasis. Case presentation: A case of RCC with Xp11.2 RCC translocations and TFE3 gene fusion was found in a pediatric patient, illustrating the catastrophic effects of ignoring the condition. The tumor developed from a local lesion to lymph metastasis (3.2-12 cm) within 4 years. Despite ongoing controversy, surgical resection remains the most common and productive approach. In this patient, renal retroperitoneal lymph node dissection and radical nephrectomy of the left kidney were performed via laparoscopic surgery. The RCC-associated Xp11.2 translocation/TFE3 gene fusions were identified by postoperative pathology. Microscopic analysis showed the presence of intravascular cancer thrombus, renal sinus invasion, and cancer necrosis. The pathological stages were confirmed as PT3aN1M0 with a negative margin. Follow-up at 5 months showed that the patient recovered without the use of any adjuvant treatments. Conclusion: Our study highlights the natural course, diagnosis, and treatment of RCC-associated Xp11.2 translocation/TFE3 gene fusions, especially the necessity of early surgery. This case may be a helpful reference for urologists in the treatment of similar cases. It also serves as a precautionary signal for patients who neglect the renal neoplasm.

The Spectrum of Renal "TFEopathies": Flipping the mTOR Switch in Renal Tumorigenesis.

The mammalian target of Rapamycin complex 1 (mTORC1) is a serine/threonine kinase that couples nutrient and growth factor signaling to the cellular control of metabolism and plays a fundamental role in aberrant proliferation in cancer. mTORC1 has previously been considered an "on/off" switch, capable of phosphorylating the entire pool of its substrates when activated. However, recent studies have indicated that mTORC1 may be active toward its canonical substrates, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and S6 kinase (S6K), involved in mRNA translation and protein synthesis, and inactive toward TFEB and TFE3, transcription factors involved in the regulation of lysosome biogenesis, in several pathological contexts. Among these conditions are Birt-Hogg-Dubé syndrome (BHD) and, recently, tuberous sclerosis complex (TSC). Furthermore, increased TFEB and TFE3 nuclear localization in these syndromes, and in translocation renal cell carcinomas (tRCC), drives mTORC1 activity toward the canonical substrates, through the transcriptional activation of the Rag GTPases, thereby positioning TFEB and TFE3 upstream of mTORC1 activity toward 4EBP1 and S6K. The expanding importance of TFEB and TFE3 in the pathogenesis of these renal diseases warrants a novel clinical grouping that we term "TFEopathies." Currently, there are no therapeutic options directly targeting TFEB and TFE3, which represents a challenging and critically required avenue for cancer research.

Coxiella burnetii inhibits nuclear translocation of TFEB, the master transcription factor for lysosomal biogenesis.

Coxiella burnetii is a highly infectious, Gram-negative, obligate intracellular bacterium and the causative agent of human Q fever. The Coxiella Containing Vacuole (CCV) is a modified phagolysosome that forms through fusion with host endosomes and lysosomes. While an initial acidic pH < 4.7 is essential to activate Coxiella metabolism, the mature, growth-permissive CCV has a luminal pH of ~5.2 that remains stable throughout infection. Inducing CCV acidification to a lysosomal pH (~4.7) causes Coxiella degradation, suggesting that Coxiella regulates CCV pH. Supporting this hypothesis, Coxiella blocks host lysosomal biogenesis, leading to fewer host lysosomes available to fuse with the CCV. Host cell lysosome biogenesis is primarily controlled by the transcription factor EB (TFEB), which binds Coordinated Lysosomal Expression And Regulation (CLEAR) motifs upstream of genes involved in lysosomal biogenesis and function. TFEB is a member of the microphthalmia/transcription factor E (MiT/TFE) protein family, which also includes MITF, TFE3, and TFEC. This study examines the roles of MiT/TFE proteins during Coxiella infection. We found that in cells lacking TFEB, both Coxiella growth and CCV size increase. Conversely, TFEB overexpression or expression in the absence of other family members leads to significantly less bacterial growth and smaller CCVs. TFE3 and MITF do not appear to play a significant role during Coxiella infection. Surprisingly, we found that Coxiella actively blocks TFEB nuclear translocation in a Type IV Secretion System-dependent manner, thus decreasing lysosomal biogenesis. Together, these results suggest that Coxiella inhibits TFEB nuclear translocation to limit lysosomal biogenesis, thus avoiding further CCV acidification through CCV-lysosomal fusion. IMPORTANCE: The obligate intracellular bacterial pathogen Coxiella burnetii causes the zoonotic disease Q fever, which is characterized by a debilitating flu-like illness in acute cases and life-threatening endocarditis in patients with chronic disease. While Coxiella survives in a unique lysosome-like vacuole called the Coxiella Containing Vacuole (CCV), the bacterium inhibits lysosome biogenesis as a mechanism to avoid increased CCV acidification. Our results establish that transcription factor EB (TFEB), a member of the microphthalmia/transcription factor E (MiT/TFE) family of transcription factors that regulate lysosomal gene expression, restricts Coxiella infection. Surprisingly, Coxiella blocks TFEB translocation from the cytoplasm to the nucleus, thus downregulating the expression of lysosomal genes. These findings reveal a novel bacterial mechanism to regulate lysosomal biogenesis.

Patients with ASPSCR1-TFE3 fusion achieve better response to ICI based combination therapy among TFE3-rearranged renal cell carcinoma.

BACKGROUND: TFE3-rearranged renal cell carcinoma (TFE3-rRCC) is a rare but highly heterogeneous renal cell carcinoma (RCC) entity, of which the clinical treatment landscape is largely undefined. This study aims to evaluate and compare the efficacy of different systemic treatments and further explore the molecular correlates. METHODS: Thirty-eight patients with metastatic TFE3-rRCC were enrolled. Main outcomes included progression-free survival (PFS), overall survival, objective response rate (ORR) and disease control rate. RNA sequencing was performed on 32 tumors. RESULTS: Patients receiving first-line immune checkpoint inhibitor (ICI) based combination therapy achieved longer PFS than those treated without ICI (median PFS: 11.5 vs. 5.1 months, P = 0.098). After stratification of fusion partners, the superior efficacy of first-line ICI based combination therapy was predominantly observed in ASPSCR1-TFE3 rRCC (median PFS: not reached vs. 6.5 months, P = 0.01; ORR: 67.5% vs. 10.0%, P = 0.019), but almost not in non-ASPSCR1-TFE3 rRCC. Transcriptomic data revealed enrichment of ECM and collagen-related signaling in ASPSCR1-TFE3 rRCC, which might interfere with the potential efficacy of anti-angiogenic monotherapy. Whereas angiogenesis and immune activities were exclusively enriched in ASPSCR1-TFE3 rRCC and promised the better clinical outcomes with ICI plus tyrosine kinase inhibitor combination therapy. CONCLUSIONS: The current study represents the largest cohort comparing treatment outcomes and investigating molecular correlates of metastatic TFE3-rRCC based on fusion partner stratification. ICI based combination therapy could serve as an effective first-line treatment option for metastatic ASPSCR1-TFE3 rRCC patients. Regarding with other fusion subtypes, further investigations should be performed to explore the molecular mechanisms to propose pointed therapeutic strategy accordingly.

An orbital perivascular epithelioid cell tumor (PEComa) in a 9-year-old boy: Case report and review of the literature.

Perivascular epithelioid cell tumors (PEComas) are a family of benign neoplasms characterized by smooth muscle and melanocytic differentiation. Orbital cases are rare. A 9-year-old male presented with a slowly growing orbital mass. Magnetic resonance imaging (MRI) revealed a well-defined orbital mass without intracranial extension. The microscopic appearance of the complete resection specimen showed large nests of epithelioid cells with wide cytoplasm containing melanin pigment and round to oval nuclei with mild cytonuclear atypia and low mitotic activity. Immunohistochemistry was positive for HMB45 and negative for melanA, smooth muscle actin, desmin and S-100 protein. Pangenomic RNA-sequencing identified an in-frame NONO-TFE3 rearrangement, and clustering data showed that the tumor's gene expression profile was grouped with other previously studied PEComas. A diagnosis of orbital pigmented PEComa with uncertain malignant potential associated with a NONO-TFE3 rearrangement was made. There was no recurrence after 1 year of follow-up.

RIT2 regulates autophagy lysosomal pathway induction and protects against α-synuclein pathology in a cellular model of Parkinson's disease.

Substantial work has been devoted to better understand the contribution of the myriad of genes that may underly the development of Parkinson's disease (PD) and their role in disease etiology. The small GTPase Ras-like without CAAX2 (RIT2) is one such genetic risk factor, with one single nucleotide polymorphism in the RIT2 locus, rs12456492, having been associated with PD risk in multiple populations. While RIT2 has previously been shown to influence signaling pathways, dopamine transporter trafficking, and LRRK2 activity, its cellular function remains unclear. In the current study, we have situated RIT2 to be upstream of various diverse processes associated with PD. In cellular models, we have shown that RIT2 is necessary for activity-dependent changes in the expression of genes related to the autophagy-lysosomal pathway (ALP) by regulating the nuclear translocation of MiT/TFE3-family transcription factors. RIT2 is also associated with lysosomes and can regulate autophagic flux and clearance by regulating lysosomal hydrolase expression and activity. Interestingly, upregulation of RIT2 can augment ALP flux and protect against α-synuclein aggregation in cortical neurons. Taken together, the present study suggests that RIT2 can regulates gene expression upstream of ALP function and that enhancing RIT2 activity may provide therapeutic benefit in PD.

The WHO 2022 Classification of Renal Neoplasms (5th Edition): Salient Updates.

The first categorization for renal tumours was made by the WHO in 1981 and included only renal cell carcinoma (RCC). After that, classification was continuously altered over five decades. The WHO 2022 Classification of Urinary and Male Genital Tumours 2022 (5th edition) is molecular-driven and contains major revisions compared to the earlier classification from 2016. This revised edition divided renal tumours into four major broad categories: clear cell renal tumours, papillary renal cell tumours, oncocytic and chromophobe renal tumours, and collecting duct tumours. 'Other renal tumours' and 'molecularly defined renal carcinomas' are two other categories that were also included. Transcription factor binding to IGHM enhancer 3 (TFE3)-rearranged, TFEB-altered, elongin C (ELOC)-mutated (formerly TCEB1)-mutated, fumarate hydratase (FH)-deficient, succinate dehydrogenase (SDH)-deficient, anaplastic lymphoma kinase (ALK)-rearranged, and SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1)-deficient renal cell carcinomas are molecularly defined entities. Eosinophilic vacuolated tumours and low-grade oncocytic tumours are classified as emerging entities. Molecularly characterized renal tumours include those with SMARCB1 deficiencies, TFE3 rearrangements, TFEB alterations, ALK rearrangements, ELOC mutations, etc. Thyroid-like follicular carcinoma, eosinophilic vacuolated tumour, and low-grade oncocytic tumour are a few emerging entities of renal tumours. Improved therapy targets for each kidney tumour can be achieved using immunohistochemistry (IHC) and molecular definition updates. This study aims to highlight new developments in the WHO 2022 categorization of renal tumours with regard to diagnostic, morphological, molecular, IHC, clinical, and prognostic updates.