Renal cell carcinoma associated with XP11.2 translocation: A case report and literature review

Abstract

Renal cell carcinoma (RCC) associated with XP11.2 translocation is an exceedingly rare subtype of RCC. A 27-year-old female presented with a 6.7cm mass and underwent a robotic-assisted left radical nephrectomy with uneventful recovery. Pathology revealed clear cell carcinoma with papillary and glandular features, positive for Melan-A, consistent with MIT family translocation renal cell carcinoma. The infrequent occurrence and its nonspecific clinical and radiological presentation results in a considerable diagnostic challenge. Given the potentially more aggressive behavior of Xp11.2 translocation RCC, particularly in adults, a thorough understanding of the tumor's genetic profile is critical for optimizing patient management and improving outcomes.

1. Introduction

Renal cell carcinoma (RCC) linked with XP11.2 translocation/transcription factor E3 gene fusion is an exceedingly rare subtype of RCCs.¹ The prevalence of such types of tumors is higher among pediatric patients, consisting of 20–40 % of RCCs. On the other hand, it is rarely observable in adults, composing 1–1.6 % of all renal tumors.² It has a non-specific presentation, while some patients present with abdominal pain, hematuria, or a newly developed abdominal mass; others might be asymptomatic and diagnosed incidentally, which might correspond to a late presentation and worse outcomes.³ The current literature regarding the associated renal masses in patients diagnosed with RCCs, specifically XP11.2 translocation/transcription factor E3 gene fusion, is confined mainly to limited case reports and small-scale observational studies. This report details a rare case of a 27-year-old female patient diagnosed with an Xp11.2 translocation/TFE3 gene fusion-positive RCC, including the description of her clinical presentation, radiological findings, laboratory data, and surgical management. Additionally, a comprehensive review of the relevant literature was performed to contextualize this rare presentation. The following case report has been prepared in accordance with the Case reports (CARE) reporting guidelines.

2. Case report

A 27-year-old female presented to the emergency department with progressive left flank pain for 3 days associated with multiple episodes of vomiting. Her past medical history is only remarkable for an excisional debridement of the right knee joint. Her social history was positive for first-degree consanguineous marriage; otherwise, it was non-contributory, and her family history was devoid of any relevant conditions. The patient's review of systems was unremarkable. Physical examination revealed a well-oriented, hydrated, afebrile patient with stable vital signs. Abdominal examination showed a soft, non-tender abdomen with mild left flank tenderness on palpation but no guarding, rebound tenderness, or palpable masses. The remainder of the physical examination was normal. Her blood workup was unremarkable except for a slight increase in WBC 11.1 × 10⁹/L.

An abdominopelvic CT scan revealed a ruptured left renal mass with associated hematoma and active bleeding. Consequently, interventional radiology was consulted, and the patient underwent lower segmental anterolateral renal artery embolization. Following the procedure, the patient was discharged and scheduled for a left renal biopsy eight weeks later. A subsequent abdominopelvic CT scan demonstrated a decrease in the size of the previously identified left renal mass, measuring 6.7 × 6.5 × 7 cm (AP x TRV x CC) (Fig. 1), compared to 11 × 9.6 × 12 cm on the prior examination. The mass exhibited multiple areas of peripheral nodular enhancement, the largest measuring 1.6 cm. The central portion of the mass displayed relatively hypodense areas with mixed densities, suggestive of hemorrhagic components. The mass abutted and displaced the anterior renal fascia anteriorly, with no evidence of vascular invasion. No enlarged local, regional, or retroperitoneal lymph nodes were identified. The delayed phase of the scan revealed normal contrast excretion through the collecting system, ureters, and urinary bladder without filling defects or focal lesions.

Fig. 1.

Abdominopelvic CT scan, both axial and sagittal cuts, demonstrates a left renal mass measuring 6.7 × 6.5 × 7 cm.

Following the aforementioned diagnostic findings, the patient was deemed a suitable candidate for surgical intervention. A robotic-assisted left radical nephrectomy was subsequently performed. The procedure proceeded smoothly, without intraoperative complications. Complete extirpation of the left kidney was achieved, as shown in Fig. 2. The patient tolerated the procedure well. Histopathological analysis of the resected tumor revealed tumor cells with clear cytoplasm and distinctive papillary and glandular architectural patterns, accompanied by microcalcifications. Immunohistochemical staining demonstrated positive expression for Melan-A and negative expression for CAIX, CD10, CK-PAN, EMA, AMACR, CD117, and HMB-45 (Fig. 3, Fig. 4). Integrating these morphological and immunohistochemical findings with the patient's age strongly suggests a diagnosis of MIT family translocation renal cell carcinoma. Genetic testing of the tumor was done viaNGS, showing MED15-TFE3 fusion, confirming the diagnosis of TFE3-rearragned renal cell carcinoma. Tumor was reaching the renal pelvis and sinus fat, and the final pathologic tumor stage is pT3a. Post-operatively, the patient's recovery was unremarkable, with no reported complications over the follow-up period of 4 months.

Fig. 2.

Gross specimen of the left kidney following robotic-assisted left radical nephrectomy.

Fig. 3.

The H&E section shows clear cell tumor arranged in tubules and papillae, with scattered psammoma bodies (arrow).

Fig. 4.

TFE-3 immunostaining shows diffuse nuclear positivity.

3. Discussion

Renal cell carcinoma (RCC) encompasses a spectrum of distinct subtypes, each exhibiting unique clinicopathological and molecular characteristics. The Xp11.2 translocation/TFE3 gene fusion-related RCC represents a rare and distinctive entity. This subtype is defined by chromosomal translocations involving the TFE3 gene on the X chromosome at position 11.2.⁴ This case report aims to contribute to the existing body of knowledge by presenting a detailed account of a patient exhibiting the unusual clinical presentation of Xp11.2 translocation RCC. By documenting and analyzing the specific clinical features, diagnostic findings, and treatment courses, we seek to enhance our understanding of this rare and often challenging-to-diagnose entity.

While representing a significant proportion of adult renal neoplasms, RCC is a comparatively rare entity in pediatric and adolescent populations. Epidemiological data demonstrates a considerably lower occurrence rate in individuals under 18, emphasizing the distinct rarity of this malignancy within younger demographics.⁵ Nevertheless, particularly the Xp11.2 translocation RCC was initially characterized in pediatrics and adolescents, typically presenting with advanced-stage disease yet exhibiting a relatively indolent clinical course in the short term.^6,7 However, the recognized patient demographic has since expanded to include adults. Furthermore, emerging evidence suggests that TFE3 rearrangement at Xp11.2 within adult RCC may predict an aggressive course of disease.8, 9, 10, 11 The presented case involved RCC in a 27-year-old female, which highlights the importance of considering this diagnosis even outside the typically recognized pediatric and adolescent age range.

Compared to other recognized subtypes of RCC, the Xp11.2 translocation/TFE3 gene fusion-related RCC often presents with more aggressive clinicopathological features at the time of initial diagnosis. This heightened aggressiveness manifests in several ways, potentially including a greater propensity for advanced tumor stage, an increased likelihood of regional lymph node involvement, and a higher incidence of distant metastases at presentation. Consequently, patients diagnosed with this specific RCC subtype often experience a less favorable clinical course and a worse prognosis compared to individuals with other forms of RCC.12, 13, 14 This disparity in outcome underscores the importance of accurate diagnosis and subtype classification in order to tailor treatment strategies and improve patient management. Jie Dong et al. conducted a retrospective single-center study from April 2010 to March 2020 aimed to determine the clinical characteristics and potential prognostic predictors.¹⁵ The study sample consisted of 24 adult patients with Xp11.2 translocation RCC aged 32 on average, with a range of 16–73 and a male-to-female ratio of 1:1, as the duration of follow-up was 35.7 months. The study results indicated that relatively high CRP/albumin ratios, fibrinogen, and distant metastasis were associated with a poor prognosis for patients with Xp11.2 RCC in adulthood. Moreover, fibrinogen levels at baseline were associated with progression-free survival in Xp11.2 RCC patients.

Furthermore, Karashima et al. reported a unique case of metachronous bilateral Xp11.2 translocation RCC in a 56-year-old female patient, representing, to the authors' knowledge, the first such documented instance in the literature.¹⁶ Seven years prior to this presentation, the patient underwent a left radical nephrectomy for clear cell RCC. Subsequent detection of a right renal tumor prompted a partial nephrectomy, initially under the presumption of recurrent clear cell RCC. However, histopathological analysis, coupled with TFE3 immunohistochemistry, fluorescence in situ hybridization (FISH), and reverse transcription-polymerase chain reaction (RT-PCR), confirmed the diagnosis of Xp11.2 translocation RCC in the right renal mass. The temporal separation of the initial clear cell RCC and the subsequent Xp11.2 translocation RCC strongly suggest a metachronous presentation of these distinct renal neoplasms.

A thorough review of the literature by Yuqing Wu et al. identified 80 studies encompassing 415 patients reporting the clinical characteristics, outcomes, and risk factors associated with overall survival and progression-free survival in Xp11.2 translocation RCC patients.¹⁷ This review demonstrated a significant association between T stage at presentation and progression-free survival (PFS), with a median PFS of 72 months. Multivariable analysis, conducted with a median follow-up of 198 months, identified age at diagnosis, T stage at presentation, and metastatic status at presentation as independent predictors of overall survival (OS). The review concluded that the T stage at presentation is the sole clinicopathological factor associated with both PFS and OS in Xp11.2 RCC patients. Furthermore, patients older than 45 years or presenting with metastatic disease exhibited a statistically significant trend towards poorer OS.

According to findings of another study that evaluated the biological behavior of Xp11.2 translocation RCCs compared to non-Xp11.2 translocation RCCs in young adults in terms of clinical outcomes over a median follow-up period of 36 months, the study, which included 16 patients with Xp11.2 translocation RCCs and 72 patients with non-Xp11.2 translocation RCCs, observed that Xp11.2 translocation RCCs were associated with higher tumor grade and pathological stage.¹⁸ Cancer-related mortality cases were comparable with 4 (4.9 %) and 3 (18.7 %) in the non-Xp11.2 translocation and Xp11.2 translocation groups, respectively. However, the two groups' Kaplan-Meier survival analysis demonstrated a statistically significant difference in cancer-specific survival. The study concluded that, among young adults, Xp11.2 translocation RCCs presented with higher tumor grades and pathologic stages than non-Xp11.2 translocation RCCs. While recurrence-free survival rates were similar between the two groups, cancer-specific survival rates were significantly lower for patients with Xp11.2 translocation RCCs.

Ged et al.‘s narrative review synthesizes current knowledge on microphthalmia-associated transcription-factor family translocation RCC (MiT-tRCC) which encompasses Xp11.2 translocation RCCs and TFE-rearranged translocations RCC.¹⁹ The hallmark X-chromosomal gene fusions involve TFE3, TFEB, TFEC, or MiTF; it is under-recognized due to the histological overlap with clear-cell and papillary RCC, and prior cytotoxic chemotherapy is the only established risk factor. Molecular profiling studies compiled in the review show that MiT-tRCCs are genomically quiet, with low tumor-mutational burden but frequent copy-number aberrations, particularly 17q gain and 9p loss, correlate with poorer OS. Surgically, partial or radical nephrectomy remains curative for localized disease, yet metastatic management is extrapolated from clear-cell RCC experience. Across small retrospective cohorts, first-line VEGF-TKIs such as sunitinib achieve modest outcomes, whereas immune-checkpoint inhibitor (ICI) regimens, particularly ICI + VEGF-TKI combinations, offer superior activity.

This case underscores the importance of a comprehensive diagnostic workup, emphasizing that a combination of immunohistochemical, cytogenetic, and molecular techniques is paramount. Immunohistochemical staining for TFE3 protein expression can provide valuable initial evidence of TFE3 involvement. Cytogenetic analyses, such as FISH, can detect specific chromosomal translocations involving the TFE3 gene. Furthermore, molecular techniques, including RT-PCR or next-generation sequencing, can identify TFE3 gene fusions and other relevant genetic alterations. When interpreted with detailed imaging studies, including computed tomography (CT) scans and magnetic resonance imaging (MRI), these techniques allow for a more precise characterization of the tumor's morphology, size, and extent of local invasion or distant metastasis.

4. Conclusion

In conclusion, we reported a rare case of Xp11.2 translocation/TFE3 gene fusion-positive renal cell carcinoma in a 27-year-old woman, which is a distinct and rare subtype with unique clinical, pathological, and molecular characteristics. The accurate diagnosis of RCC, particularly the less common subtypes such as Xp11.2 translocation/TFE3 gene fusion-related RCC, necessitates a multidisciplinary approach. Effective collaboration among urologists, pathologists, radiologists, oncologists, and other relevant specialists is crucial for integrating diverse diagnostic modalities and arriving at a definitive diagnosis. The present case, involving RCC in a 27-year-old female, adds to the expanding body of evidence regarding RCC in adults and highlights the critical need for careful consideration of the specific histological subtype and associated genetic alterations, particularly TFE3 rearrangement. Accurate subtyping is essential for establishing a precise diagnosis, providing crucial prognostic information, and guiding individualized treatment strategies. Given the potentially more aggressive behavior of Xp11.2 translocation RCC, particularly in adults, a thorough understanding of the tumor's genetic profile is critical for optimizing patient management and improving outcomes. This case reinforces the value of meticulous diagnostic evaluation and underscores the ongoing need for further research to refine our understanding of this rare and challenging entity.

CRediT authorship contribution statement

Bader Alsaikhan: Writing – review & editing, Supervision, Conceptualization. Saud AlHussayen: Writing – review & editing, Investigation, Data curation. Ebtesam Almajed: Writing – original draft, Resources, Project administration, Formal analysis, Data curation, Writing – review & editing. Abdullah Alghuraibi: Writing – original draft, Project administration, Methodology. Khaled Almodeth: Writing – review & editing, Writing – original draft, Data curation. Noura Al Oudah: Data curation, Writing – review & editing, Abdullah Alkhayal, Resources. Abdulrahman K. Alabdulsalam: Data curation, Writing – review & editing.

Availability of data and materials

The data used in the case report are available on reasonable request.

Funding

No external funding was received for this case study.