Metastatic Melanoma of the Urinary Bladder in the Era of Targeted Therapy

Case Report 

Metastatic Melanoma of the Urinary Bladder in the Era of Targeted Therapy

Corresponding author Dr. Luke Wang, 823-865 Centre Road, Bentleigh East, Victoria, 3165, Australia,
Tel: +61 411843415; Fax: (03) 9928 8278; Email: drlukewang@gmail.com

Abstract

Metastasis of malignant melanoma to the urinary bladder is a rare clinical entity. Here we present the case of a 78 year-old man with metastatic melanoma in his bladder found on surveillance cystoscopy for previous bladder urothelial carcinoma, in the context of concurrent BRAF and MEK inhibitor therapy for melanoma metastasis to other sites. The bladder lesions were histologically confirmed to be melanoma, but despite lower urinary tract symptoms he was managed expectantly and succumbed to his disease some months later. This is only the second case in the English literature reporting bladder metastases from malignant melanoma with concurrent treatment of targeted therapy. There has been recent promise of longer survival amongst patients with metastatic melanoma afforded by these new therapies, and accordingly we may see a rise in incidence of stable metastases to rarer sites of spread and a need for improved local control of metastatic sites. Although we did not treat our patient’s bladder metastasis more aggressively due to his guarded prognosis, this case highlights the potential for metastasis to rarer sites in the context of increased survival from new therapies and the lack of relevant targeted intravesical treatments for bladder metastases.
Keywords: Melanoma; Metastases; Bladder; Urology; Cystoscopy
Introduction

Since 1953, only approximately 24 cases over the duration of 52 years have been reported making metastatic melanoma to the urinary bladder a rare clinical entity[1]. These tumours typically present with painless macroscopic haematuria but are otherwise more frequently discovered at autopsy [1,2]. This suggests that in the majority of cases, treatment would only be expectant due to the very limited survival of this patient cohort. The discovery of PD-1 inhibitors and the use of targeted therapies such BRAF and MEK inhibitors have shown great promise in enhancing survival. Here we present the case of a 78 year-old man with deposits of metastatic melanoma within his bladder found on surveillance cystoscopy for previous bladder urothelial carcinoma 25 years following excision of the primary lesion. This occurred in the context of treatment with both BRAF and MEK inhibitors for known metastatic melanoma  o other systemic sites. To the best of our knowledge, there is only one other report of metastatic melanoma to the urinary bladder in the context of concurrent treatment with targeted therapy in the English literature [3].Case Report

A 78 year-old man presented for routine annual surveillance  cystoscopy for previously diagnosed low-grade non-invasive papillary urothelial carcinoma four years prior. Previous surveillance had revealed no recurrence following initial endoscopic resection of his bladder malignancy. Other medical history included near total pancreaticoduodenectomy for intraductal papillary mucinous neoplasm of the pancreas, type 2 diabetes mellitus, atrial fibrillation, hypertension, and melanoma. He had a smoking history. In the few months leading up to his presentation he had been experiencing urinary frequency and nocturia, but no haematuria. Urine cytology was unremarkable.

The patient’s primary malignant melanoma was initially excised from the scalp 25 years prior and histology showed a nodular subtype with 4mm Breslow thickness, Clark level IV and with no lymphovascular or perineural invasion. Metastatic melanoma had been diagnosed 5 months prior to his presentation to our service with positron emission tomography (PET) avid lesions found in the occiput, mediastinum and right lung. A combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib was commenced as part of a clinical trial at another institution. There was minimal response to this therapy on follow-up computed tomography (CT) scans at the time of his presentation.At flexible cystoscopy, multiple small raised black-pigmented lesions were scattered throughout the bladder (Figure 1).  ubsequent biopsies of these lesions at rigid cystoscopy confirmed metastatic melanoma with the presence of malignant epithelioid melanocytes staining strongly for Melan A immunoperoxidase (Figure 2).

Figure 1. Multiple raised black pigmented lesions seen on flexible cystoscopy (a); lesion near the right ureteric orifice (b).

Given the advanced stage and overall treatment resistance of his disease, a multi-disciplinary team consensus decision was made for no further active management of his bladder metastases. The patient succumbed to respiratory complications of his melanoma three months later.

Figure 2. Malignant melanocytes staining strongly for Melan A immunoperoxidase.

Discussion

Secondary tumours of the bladder represent just 2% of all bladder tumours with most due to local invasion commonly by cancers of the colon, prostate, rectum and cervix [4]. Distant metastases to the bladder arise from cancers of the stomach, skin, lung and breast.4 Although melanoma itself is a common malignancy with an incidence of 15-25 per 100,000, with  Australia having the highest incidence in the world5,6, metastasis to the bladder is rare. Only 24 cases have been reported in the literature over a half century with most involving some form of active treatment (Table 1) [3,7-9]. These tumours can present with painless macroscopic haematuria but they are often asymptomatic and more frequently discovered at autopsy [2].

Management options for bladder metastases include no active treatment, endoscopic resection and systemic therapy, all aimed generally at symptom relief. Radical and partial cystectomy have been reported for select patients with solitary metastasis, but this would be a rare situation [7,9]. Treatment would traditionally account for patient performance status as well as the context of the short 6-12 months median survival of metastatic melanoma [6].

Major advances have been made recently in the treatment of metastatic melanoma and key mutations resulting in alterations in molecular pathways driving melanoma cell proliferation have been identified. Successful treatment with targeted agents such as BRAF and MEK inhibitors have followed, along with immune checkpoint blocking agents, such as antibodies to PD-1 and PD-L1, with an extension in survival beyond 2 years for many patients [6,10]. This success could see symptomatic bladder metastases encountered more frequently and necessitating intervention. In this exciting landscape of promising systemic treatments for metastatic melanoma, the bladde remains unique in that intravesical lesions could be treat-ed directly with potentially less systemic toxicity if intravesical modes of delivery for these novel agents can be found.

Table 1. Previously reported cases of malignant melanoma to the urianry bladder.

* in context of targeted therapy; LUTS – Lower Urinary Tract Symptoms; TURBT – Transurethral Resection of Bladder  umour; BCG – Bacillus- Calmette-Guerin

Conclusion

Recent advances in new targeted therapies for the treatment of metastatic melanoma have seen prolonged survival amongst patients with advanced melanoma. This may lead to a rise in incidence of stable metastases to urologic organs requiring treatment for symptomatic relief, and potential intravesical delivery of the targeted agents may be of benefit in these patients.

Disclosure of sources of financial support

None

Acknowledgement

The authors gratefully acknowledge Dr. Stephen Bare, MBBS, for acquiring and annotating the histology images.

References

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3.Rishi A, Anderson TA, Kirschenbaum AM, Unger PD. Metastatic Malignant Melanoma to Urinary Bladder: A Potential Pitfall for High-Grade Urothelial Carcinoma. Int J Surg Pathol. 2014, 22(4): 347-351.

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6.Schadendorf D, Hauschild A. Melanoma in 2013: Melanoma– the run of success continues. Nat Rev Clin Oncol. 2014, 11(2):75-76.

7.Efesoy O, Cayan S. Bladder metastasis of malignant melanoma: a case report and review of literature. Med Oncol. 2011, 28 (Suppl 1):S667-669.

8.Paterson A, Sut M, Kaul A, Altieri V, Mutch F et al. Metastatic malignant melanoma of the urinary bladder: Case report and literature review. Cent European J Urol. 2012, 65(4): 232-234.

9.Wisenbaugh ES, Stanton ML, Grimsby GM, Tyson MD, Castle EP. Metastatic malignant melanoma to the bladder: a case series. Curr Urol. 2012, 6(1): 53-56.

10.Menzies AM, Long GV. Recent advances in melanoma systemic therapy. BRAF inhibitors, CTLA4 antibodies and beyond. Eur J Cancer. 2013, 49(15): 3229-3241.

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