Adult Xp11.2 translocation renal cell carcinoma managed effectively with pazopanib

Abstract

Xp11.2 translocation renal cell carcinoma (TRCC) is a rare and aggressive variant of renal cell carcinoma (RCC) when presenting in adults. We report a case of a man in his early 40s who was diagnosed with stage III Xp11.2 TRCC and underwent radical nephrectomy. Seven months following the surgery, an adrenal nodule and bilateral pulmonary nodules were discovered. He underwent cryoablation of the adrenal nodule and systemic treatment with daily pazopanib. He displayed stable disease for approximately 6 years. Following this period, multiple hospitalisations interrupted daily pazopanib therapy resulting in progression of disease. His regimen was then changed to ipilimumab and nivolumab, followed by current daily therapy with axitinib. The patient now shows stable disease in his 10th year after diagnosis. This case study demonstrates the efficacy of pazopanib for metastatic Xp11.2 TRCC and warrants further investigation to supplement the guidelines regarding the use of targeted therapy for TRCC.

Background

Xp11.2 translocation renal cell carcinoma (RCC), a rare subtype of RCC, has gained significant clinical interest in the past two decades. In 2004, the WHO formally accepted Xp11.2 translocation RCC (TRCC) as a distinct entity within the renal tumour classification system, however it is now subclassified under the MiT family TRCC in the updated 2016 WHO classification.^{1 2} Other more common types of RCC include clear cell (65%–70%), papillary (15%–20%) and chromophobe (5%–10%).³ Xp11.2 translocation compromises around 25% of paediatric RCC, but only contributes to about 1.6%–5.0% of all reported adult RCC.^4–6 It is hypothesised that the frequency of this TRCC is underestimated as it morphologically overlaps with clear cell and papillary RCC and therefore may be misdiagnosed as these more common subtypes.^{5 7}

Xp11.2 TRCC results from fusion of transcription factor E3 (TFE3) gene, located on the short arm of chromosome X, to numerous genetically identified fusion partners. Among these, the three most common partners are PRCC on 1q21, ASPL/ASPSCR1 on 17q25 and SFPQ/PSF on 1p34, with many new genes still being discovered.^{7 8} One of these translocations resulting from the fusion combination of ASPL/ASPSCR1 and TFE3 shares the same chromosomal breakpoint (Xp11.2, 17q25) as the paediatric soft tissue neoplasm, alveolar soft part sarcoma (ASPS), known for its chemotherapy refractory course.^{7 9}

There are only a few case reports and observational studies on systemic therapy of advanced Xp11.2 TRCC, most of which involve the use of sunitinib.^{9 10} This is in part due to the rarity of the disease itself along with poorly understood molecular pathophysiology. Here, we present a case of an Xp11.2 TRCC, discuss the clinical approach as guided by cytogenetic classification and management offered with pazopanib.

Case presentation

A man in his early 40s initially presented to his primary care physician’s (PCP) office for painless gross haematuria. Records from his PCP’s office could not be obtained, however as part of the workup he underwent renal ultrasound which was noted to be abnormal and was referred to our healthcare system for further evaluation. He had no other clinical complaints. His medical history was unremarkable to this case. He was a current smoker with a 24-pack year history and only used alcohol socially, at the time of presentation. Complete blood count, renal function test including calcium and liver function test were within normal limits. A contrast enhanced CT scan of the abdomen/pelvis detected a large complex heterogeneously enhancing mass measuring 10.7 cm in the mid-to-lower pole of right kidney infiltrating Gerota’s fascia (figure 1A, B), patent right renal vein, no perinephric adenopathy and mildly prominent retroperitoneal lymph nodes. Chest X-ray did not visualise signs of distant metastasis or any other abnormal findings.

Figure 1.

Large complex heterogeneously enhancing right renal mass identified on abdominal CT scan in (A) coronal and (B) transverse view.

Based on the CT findings, a clinical diagnosis of RCC was made and he promptly underwent laparoscopic right radical nephrectomy. Pathological evaluation demonstrated Xp11.2 TRCC, Fuhrman nuclear grade 3, 9.3 cm in size, with large vein embolus but no invasion of the renal sinus or perinephric adipose tissue. Margins of resection were negative for carcinoma. Diagnosis of stage III (pT3a, cN0, cM0) Xp11.2 TRCC was made based on TFE3 immunostaining which showed weak-to -moderate intense staining on the biopsy. American Joint Committee on Cancer’s 7th edition of the Cancer Staging Manual was referenced for staging.

Outcome and follow-up

A 7-month postoperative follow-up abdominal CT scan showed no recurrence of disease at the surgical bed but a new 2 cm left adrenal nodule was detected. CT scan of the chest showed multiple 3 mm bilateral lung nodules with mild prominence of hilar lymph nodes concerning metastatic disease. CT-guided biopsy of the left adrenal nodule confirmed metastatic adenocarcinoma of previously diagnosed RCC, with positive TFE3 stain, confirming progression to stage IV Xp11.2 TRCC. At this time, the patient underwent cryoablation of the left adrenal nodule and was promptly started on pazopanib therapy daily.

For the next 5 years, his bi-yearly CT scan of the chest/abdomen/pelvis showed no progression of disease, no recurrence in the surgical bed and stable appearing lung nodules. He remained on daily pazopanib therapy with no significant side effects.

However, nearing his 6th year of progression-free survival, he required five admissions for alcohol-induced pancreatitis and alcoholic hepatitis over the course of 1.5 years, with one admission requiring intensive care unit stay. This interrupted his pazopanib therapy for about 5 months during this period. Follow-up CT scan then detected metastatic disease involving multiple ribs bilaterally, as well as a conglomeration of new nodules of the left lower lung, partially confluent, measuring 7 cm. Ultrasound-guided biopsy of the rib lesion confirmed metastatic RCC, which also prompted him to quit drinking alcohol.

At this time, in his 7th year since diagnosis, the decision was made to switch his regimen to ipilimumab and nivolumab due to disease progression. He also received palliative radiation to his symptomatic rib lesions. He received ipilimumab, nivolumab and zoledronic acid for the next four cycles without complications. However, there were concerns of immunotherapy-induced hepatitis due to elevated liver enzymes which required dose reduction of nivolumab in the last two cycles of his nine cycles of treatment. Imaging revealed stable disease post immunotherapy, however pancreatic and biliary ductal dilation were evident. Benign stricture was confirmed by endoscopic retrograde cholangiopancreatography with biopsy, and the liver enzymes normalised after placing a stent.

Axitinib was started after he completed immunotherapy a year ago which he continues to take daily into his 10th year since diagnosis. His liver enzymes have been within normal limits and CT scan of the chest/abdomen/pelvis 2 weeks ago showed stable disease with no progression.

Discussion

Classification of RCC historically has largely been based on morphology and histology; however, with the use of immunohistochemistry (IHC) and cytogenetics, TRCC has been identified as a distinct yet an uncommon variant.

Xp11.2 has shown a strong female preponderance, with median age of presentation between 41 and 43 years in adults.^{5 10} It is also associated with aggressive tumour behaviour and advanced stages at the time of diagnosis.^{7 11} The only known risk factor for development of this neoplasm is previous cytotoxic chemotherapy exposure, specifically demonstrated in children.¹² Although a majority of patients will have no history of cytotoxic exposure, it highlights the importance of this information when taking a history and evaluating a patient with a suspected renal neoplasm. Many studies recommend consistent use of IHC with TFE antibodies as the absence of this step may result in misclassification due to the morphological homogeneity between Xp11.2 translocation and the clear cell RCC.^{5 7} A study by Zong et al further emphasises a targeted workup specifically in young/middle age patients (<45) with metastatic RCC and those with typical clear cells with papillary histopathological features.⁵ However, the use of IHC alone to investigate TFEB gene rearrangements is limited by the intrinsic characteristics of the technique which include fixation dependence and lot-to-lot variation of the antibody used. Furthermore, positive IHC for TFEB can occur in other types of RCC including papillary type 2 tumours associated with hereditary leiomyomatosis and renal cell cancer and hybrid tumours associated with Birt-Hogg-Dubé syndrome. In order to mitigate these limitations, utilisation of break apart fluorescence in situ hybridization should be used for definitive diagnosis of Xp11.2 TRCC.¹³ Our case study highlights the importance of considering this rare variant when conducting histopathologic and molecular studies of all renal neoplasms.

Surgery, with nephron sparing or radical nephrectomy, remains the mainstay of treatment for localised RCC (stages I–II), irrespective of the subtype. Systemic adjuvant therapy or immunotherapy after complete surgical resection of localised clear cell RCC has widely been studied and it is suggested for use only in high-risk clear cell RCC. However, these studies did not include or stratify the analysis specifically for TRCC.^14–16 Management of advanced clear cell RCC with the use of checkpoint inhibitors and tyrosine kinase inhibitors targeting vascular endothelial growth factor (VEGF) receptor is guided by high-quality evidence, however there are no clinical trials suggesting the use of these agents in TRCC. Furthermore, most of the data gathered through observational studies mainly focus on the use of sunitinib in this subgroup.

Chouerie et al retrospectively observed 15 patients diagnosed with metastatic Xp11.2 TRCC treated with anti-VEGF therapy which included sunitinib, sorafenib and monoclonal anti-VEGF antibodies.¹⁰ Three patients had a partial response to therapy, seven demonstrated stable disease and five developed progressive disease. The median progression-free survival and overall survival was 7 and 14.3 months, respectively, at a median follow-up of 19.1 months. Similarly, Al-Daghmin et al reported six cases of metastatic TRCC treated with sunitinib, where one had complete response, one had disease progression and four had stable disease for an average of 19 months.¹⁷ However, use of pazopanib, a similar anti-VEGF agent, has not been reported yet in this patient population. While our patient had progression-free disease for 5 years on pazopanib, the limitation in our study was the use of pazopanib in a single patient. Besides anti-VEGF therapy, the use of immune checkpoint inhibitors has also been reported by Boilève et al where they conducted a retrospective study on 24 patients with MiTF family TRCC treated with immune checkpoint inhibitors as a second-line treatment after VEGF receptor inhibitors. The results of this study showed a clinical response in 16.7% of patients and a disease control rate of 29%, when stable disease was included.¹⁸ Further investigation is warranted in the use of pazopanib and other agents that may provide the greatest benefit within this patient population.

Understanding the oncogenic effects of translocations in the tumorigenesis of Xp11.2 RCC would be beneficial in establishing targeted therapy. Molecular studies have shown that TFE3 belongs to the overarching MiT transcription factor family which also includes TFEB, TFEC and MiTF. The MiT family regulates numerous molecular pathways which are commonly related to cell growth and differentiation.¹⁹ More specifically, dysregulation of TFE3 is proposed to be oncogenic through its interaction with a constitutively active promoter and subsequent effects on numerous pathways that it regulates such as transforming growth factor-β activation, MET protein expression and Rb-dependent cell cycle arrest.^19–22 As a result, therapy targeting these pathways have been proposed as possible regimens wherever systemic therapy is warranted. TFE3 dysregulation has also been found to activate mTORC1, a regulator of protein synthesis. This has prompted investigation into this protein as an additional proposed target of therapy.^{23 24} In vitro studies have also shown that selective MET tyrosine kinase inhibitors result in diminished tumour growth in a variety of cancers.^{21 25} This is a possible mechanism which explains the favourable response of pazopanib, a tyrosine kinase inhibitor, in this patient.

This case study demonstrates the efficacy of pazopanib in metastatic Xp11.2 TRCC. Our patient experienced a progression-free survival for approximately 5 years on pazopanib. The heavy use of alcohol causing repeated episodes of pancreatitis and alcoholic hepatitis lead to an interruption in pazopanib therapy, ultimately causing progression of disease requiring a change in regimen. For the past 1 year, he has been on axitinib and has shown stable disease, the use of which has been supported by Nishimura et al.²⁶ Further studies including clinical trials on systemic therapy for advanced Xp11.2 TRCC alone or as a stratified analysis under other non-clear cell RCC should be performed to inform the comparable efficacy among different targeted therapy, including pazopanib.

Learning points.

• Xp11.2 translocation renal cell carcinoma (TRCC) is a common pediatric variant of renal cell carcinoma (RCC), when found in adults it is associated with aggressive tumor behavior and advanced stages at the time of diagnosis.

• The use of immunohistochemistry is recommended for diagnosis due to historical misclassification of Xp11.2 TRCC with clear cell RCC.

• This is a case of Xp11.2 TRCC with approximately 6 years of favorable response to pazopanib daily therapy. Interruption in daily treatment due to recurrent hospitalisations leads to progression of disease.

• This case study demonstrates the efficacy of pazopanib for metastatic Xp11.2 TRCC and warrants further investigation into targeted therapy.

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