Clinicopathologic, treatment and prognosis study of 46 Xp11.2 translocation/TFE3 gene fusion renal cell carcinomas

A retrospective was performed for all the Xp11.2 translocation RCC patients treated at Renji Hospital, School of Medicine, Shanghai Jiaotong University from January 2014 to April 2020. The diagnosis and grading criteria of Xp11.2 translocation RCC in the current study were based on the 2016 WHO classification [5]. Clinical information including age, sex, symptoms of onset, tumour diameter, tumour location, pathological information, and surgical information was reviewed. Follow-up data were collected for the original surgeons.

Tumour size and gross appearance were obtained from the original pathologic reports, while the TNM stage was assessed according to the 8th edition of AJCC TNM staging [6]. Paraffin sections of all selected cases were reviewed by two independent pathologists (ZW and QL) for re-evaluation of nuclear grade according to ISUP criteria, as well as the histological pattern [7].

The clinical data are summarized in Table 1. In total 46 patients were included in the current cohort, including nineteen male patients and twenty-seven female patients. The mean age was 39 years (ranging from 15 to 72). The tumour was accompanied by clinical symptoms at the time of diagnosis in 9 patients, which including four patients who complained of lumbar pain, four patients with haematuria and one patient with severe pelvic pain due to metastatic lesions. None of these patients in the cohort had developed any other malignancies before. However, two patients had lymphatic metastasis, one had bone metastasis, one had lung metastasis and one had both lymphatic and hepatic metastasis before surgery.

Sixteen patients underwentunderwent radical nephrectomy, including three cytoreductive surgeries, while thirty patients received partial nephrectomy either by laparoscopic or open approaches. Retroperitoneal lymph node dissection was performed for patients with suspected lymphatic metastasis or a rather large tumour size (≥ cT2).

All tumours examined were unilateral and unifocal. The maximum diameter of the tumours ranged from 12 to 109 mm, and the median maximum diameter was 40 mm (IQR 18.5 ~ 60.5).

Most tumours arose in the renal cortex, with soft or firm texture. Although there was no distinctive gross appearance, in most Xp11.2 translocation RCC cases, the cut surface colouration was usually yellowish, which was different from the typical golden yellow colour in clear cell carcinoma (Fig. 1). Beyond that, haemorrhages and necrosis were occasionally noted.

In most cases, the histologic appearance of Xp11.2 translocation RCC is a neoplasm with mixed tubular and papillary structure, with cells of different morphology including clear or eosinophilic cytoplasm. Psammoma bodies, lymphocytes infiltration, and necrosis were found in most Xp11.2 translocation RCCs (Fig. 2A–E).

In the current cohort, all cases showed positive TFE3 staining. Diffuse nuclear staining was detected under microscope. The nuclei showed diffuse, strong staining for TFE3.

In FISH analysis, TFE3 gene rearrangement was detected by using a dual-colour break-apart FISH probe (Anbiping Inc., Grangzhou, China) according to the manufacturer's recommendations (Fig. 2F).

Patients were followed up for 4 to 74 months, with a median follow-up duration of 30.5 months. By the ultimate follow-up deadline, 6 patients had tumour recurrence or metastasis, among whom 4 patients died of the disease. The total median overall survival and cancer specific survival were 30.0 months and 24.0 months, respectively. The 1-year, 3-year and 5-year OS rates were 97.4%, 88.8%, and 88.8%, respectively.

In patient #4, who underwentunderwent laparoscopic partial nephrectomy for a 68 mm tumour with a negative surgical margin in pathologic diagnosis, local recurrence was found 4 months after surgery, and underwent another radical nephrectomy. The patient remained alive untill the end of follow-up. In patient #25, who underwent laparoscopic partial nephrectomy for a 32 mm tumour, lung metastasis was found 6 months after surgery. The patient received Axitinib for targeted therapy thereafter but still died 24 months after the initial surgery. Patient #29 was a pT1aN0M1 patients with bone metastasis who underwent both laparoscopic partial nephrectomy and resection of bone metastatic lesions. The patient received Pazopanib one month after surgery and combined with Nivolumab since 2019. The patient remained alive untill the end of follow-up. In patient #37, a T1aN0M0 patient underwent laparoscopic partial nephrectomy, multifocal metastases including lung, bone and lymph nodes were found 22 months after surgery. The patient received targeted therapy and died 34 months postoperatively. In patient #44, a pT1bN1M1 patient with liver and lymph node metastasis, multifocal metastasis was found in lung and liver shortly after cytoreductive nephrectomy, and the patient died 8 months after surgery. In patient #46, a pT2aN0M1 patient with lung metastasis treated with cytoreductive nephrectomy, the lung metastatic focus was enlarged despite of target therapy, and the patient died 10 months after surgery.

By evaluating potential survival factors, such as age, sex, tumour location, tumour size, T classification, lymph node metastasis, distal metastasis utilizing univariable Cox regression analysis and Kaplan–Meier analysis, we found that patients with symptoms when diagnosed (p = 0.019), lymph node metastasis (p = 0.002) and distal metastasis (p = 0.020) were associated with a poor oncologic outcome.