Abstract

Background:Brain metastases are the most common adult brain tumors, frequently arising from primary tumors in the lung, breast, skin, kidneys, and colon. Transitional cell carcinoma (TCC), the most common type of urinary bladder cancer, is a rare cause of brain metastasis with an ominous prognosis.

Case Description:A 68-year-old female presented with right-sided paresis and focal motor seizures of her right upper and lower extremities 14 years after being diagnosed and treated for primary TCC of the urinary bladder with gemcitabine-based chemotherapy. MRI imaging revealed a 3.1 × 3.1 × 2.7 cm heterogeneously enhancing mass located along the posterior aspect of the left frontal convexity. The lesion was accessed using a transsulcal approach and was surgically debulked along the motor cortex with motor strip mapping, followed by adjuvant whole-brain radiation therapy. Pathological examination confirmed metastatic carcinoma with features of TCC, a rare entity among metastatic brain tumors.

Conclusion:Brain metastases may present several years later in patients with TCC of the urinary bladder who have been treated with surgery and chemotherapy. Chemotherapeutic agents that penetrate the blood–brain barrier, such as gemcitabine, may delay development of cerebral metastasis from primary TCC of the urinary bladder.

Keywords: Brain tumor, cerebral, intracranial, metastatic, transitional cell carcinoma, urinary bladder cancer

BACKGROUND

Brain metastases are the most common adult brain tumors and account for 13–39% of intracranial tumors.[ 34 61 100 ] The incidence rate of all forms of brain metastasis in the United States is approximately 170,000 per year.[ 52 ] It is estimated that 20–40% of all cancer patients develop some form of intracranial metastases.[ 34 68 86 ] The most common adult primary tumors that metastasize to the brain, in decreasing order of frequency, are lung, breast, skin (melanoma), renal, and colon cancers.[ 49 61 100 ]

The estimated incidence of new urinary system cancer cases in 2009 is 131,010, of which 70,980 (54.2%) stem from the urinary bladder, 57,760 (44.1%) stem from the kidney and renal pelvis, and 2,270 (1.7%) stem from the ureter and other urinary organs.[ 43 ] Transitional cell carcinoma (TCC) accounts for over 90% of the reported urinary bladder cancers in the United States, while less than 5% result from squamous cell carcinomas (SCC), and less than 2% result from adenocarcinomas.[ 89 ] Urinary bladder cancer has great potential to metastasize, and sometimes the frequency of metastasis can be as high as 67%.[ 48 ] A 2011 retrospective study of 392 patients with urinary bladder cancer reported the most common sites of metastasis to be the lymph nodes (104 patients, 69%), followed by bone (71 patients, 47%), lung (55 patients, 37%), liver (39 patients, 26%), and peritoneum (24 patients, 16%).[ 84 ] It is rare for TCC of the urinary bladder to metastasize to the brain, and reported incidences in patients with urinary bladder cancer range anywhere from 0% to 7%.[ 17 ] The prognosis for patients with brain metastasis from urinary bladder cancer is ominous, regardless of treatment. Treated patients have a median survival of 2–4 months,[ 58 77 ] while untreated patients’ survival ranges from several days to 1.75 months.[ 1 23 45 58 ] We present an unusual case of a 68-year-old female with a history of urinary bladder cancer 14 years prior that was discovered to have a left frontal mass after presenting with seizures and right-sided paresis.

CASE DESCRIPTION

History

A 68-year-old, right-handed, Caucasian female nurse, with a past medical history of TCC of the urinary bladder, presented with a chief complaint of right-sided weakness and seizures. The patient was diagnosed with urinary bladder cancer in 1996. At that time, she was treated with forty-five cycles of gemcitabine, paclitaxel, and cisplatin chemotherapy. In 2005, she received local radiation therapy to the urinary bladder. In 2006, liver metastases were discovered, and the patient responded well to palliative chemotherapy with six additional cycles of cisplatin with gemcitabine. In 2008 she presented with hydronephrosis secondary to a large distal right ureteral recurrence of the TCC. The patient underwent a laparoscopic nephroureterectomy and cystoscopy that year. The patient denied tobacco, alcohol, or drug abuse. At her latest admission in 2010, the patient reported a 2-week history of right arm and leg weakness and a 1-day history of uncontrollable shaking of her right upper and lower extremity. The shaking was brief and resolved spontaneously. The patient denied loss of consciousness, nausea, vomiting, dysarthria, headaches, visual changes, cognitive changes, or difficulty ambulating.

Neurologic exam and imaging

Neurologic examination revealed right-sided gait disturbance, as well as proximal more than distal paresis of muscle groups in her right upper and lower extremity (4 to 4+/5). The medical exam and the remainder of the neurologic exam were without focal deficits.

Initial imaging by the emergency room, noncontrast enhancing computed tomography (CT) of the brain, revealed an isodense lesion of the left frontal lobe with associated vasogenic edema [ Figure 1 ]. Magnetic resonance imaging (MRI) of the brain showed a 3.1 × 3.1 × 2.7 cm heterogeneously enhancing mass located along the posterior aspect of the left frontal convexity [ Figure 2 ]. The patient was placed on high-dose corticosteroids and antiepileptics. The metastatic evaluation, which included contrast-enhanced CT of the chest, abdomen, and pelvis, showed no evidence of local recurrence, lymphadenopathy, or metastatic disease. The patient elected for craniotomy and resection of the tumor with motor strip mapping.

Figure 1

Precontrast axial CT scan showing a left frontal lobe lesion with surrounding edema (a), Postoperative precontrast axial CT scan status after left frontoparietal craniotomy showing a residual area of hypodensity in the operative bed caused largely by edema (b)

Figure 2

Precontrast axial T1-weighted MRI (a), postcontrast axial T1-weighted MRI (b), precontrast sagittal T1-weighted MRI (c), postcontrast sagittal T1-weighted MRI (d), coronal T1-weighted MRI (e), axial T2-weighted MRI (f), axial FLAIR image showing a solitary lesion with surrounding edema (g)

Operation

The tumor was accessed via a left parietal craniotomy after the outline of the tumor was marked with the frameless stereotactic system (Germany). A transsulcal approach was used to access the tumor, which was located just anterior to the motor strip. Intraoperative findings consisted of an extra-axial left frontal–parietal tumor that was gray in color with a firm and rubbery consistency. There was a surgical plane around the tumor and we achieved a near complete resection. The posterior margin of the tumor was unresectable given motor strip mapping indicated motor cortex territory, so we left a small rim of tumor to avoid causing the patient further weakness.

Pathological findings

Pathological examination included a histologic analysis of three portions of firm tan-white tissue, measuring 1.0 × 1.0 × 0.2 cm in aggregate frozen section. A second brain biopsy, consisting of firm tan-white tissue measuring 3.5 × 2.5 × 0.7 cm in aggregate, was analyzed. The final pathological diagnosis of our left parietal brain tumor biopsy was metastatic carcinoma with features of TCC [ Figure 3 ].

Figure 3

Groups of poorly differentiated papillary urothelial carcinoma cells invading into brain parenchyma. (a): ×100, (b): ×400

Postoperative course

On awakening, the patient showed mild expressive aphasia and weakness, both of which improved on discharge on postoperative day five. No significant complicating factors were noted on postoperative MRI scan [ Figure 4 ]. She then underwent adjuvant whole-brain radiation therapy. At her 12-month follow-up, the patient had residual weakness of her right upper extremity, a condition that had improved only slightly since surgery. She evidenced no progression of metastatic disease, and there was no increase in the size of the residual tumor.

Figure 4

Postoperative precontrast axial T1-weighted MRI (a), Axial T2-weighted MRI (b), Sagittal T1-weighted MRI (c), Coronal T1- weighted MRI status after left frontoparietal craniotomy showing no significant complicating factors (d)

DISCUSSION

The first case of TCC metastasis to the brain was reported by Lower and Watkins in 1924, where they presented a 48-year-old male patient without a history of tobacco use. Complaining of irritative urinary symptoms, he was found to have hematuria and proteinuria in a physical examination, which had been required for obtaining life insurance. Shortly after a cystectomy was performed, and after pathological examination confirmed malignant transitional epithelial cells, the patient developed difficulty with ambulation and dysarthria. He was referred to the eminent neurosurgeon, Dr. Walter E. Dandy, who extirpated a solitary metastatic tumor measuring 2 cm from the right internal capsule. The patient died 10 months later due to recurrence of brain metastases.[ 56 ]

Historical incidences of TCC metastases have been low. In 1988, Graf reported four patients (1.7%) with brain metastases originating from urinary bladder cancer among the 230 cases of brain metastases taken from a sample of 15,000 autopsies between 1969 and 1984.[ 33 ] Our review of the literature revealed 290 reported cases of TCC metastasis to the central nervous system [ Table 1 ]. There are 54 case reports and small case series (up to three patients) reporting intracranial metastasis of TCC [ Table 2 ]. Of these, the clinical presentation of central nervous system symptoms from intracranial metastasis preceded the diagnosis of urinary bladder cancer in 11 cases (20.4%).[ 12 14 17 19 29 40 44 71 74 78 82 ] The distribution among all cases tended to be skewed toward males and single or solitary lesions over multiple metastases. Metastasis to the frontal lobe seemed to be the most common location of single or solitary lesions, followed by the temporal and parietal lobes. The occipital lobe typically had the least number of metastases. Gross hematuria and irritative urinary symptoms were the most common presentations for urinary bladder cancer. Common neurologic symptoms in patients with TCC intracranial metastasis included headache, nausea, vomiting, speech impairment, ataxia, cognitive impairment, dizziness, and hemiparesis.

Table 1

Incidence of transitional cell carcinoma of the urinary bladder to CNS metastatic sites

Table 2

Number of case reports and small case series (up to three patients) reporting intracranial metastasis of transitional cell carcinoma

Treatment modalities for brain metastases consist of surgery, systemic chemotherapy, and radiation therapy in the form of whole-brain radiation or stereotactic radiosurgery. These treatment methods may be used alone or in combination. Reports from various authors demonstrate the differences among modalities for the treatment of TCC brain metastases [ Table 3 ]. The largest series of patients with TCC brain metastases was reported in 2010 by Fokas et al., who analyzed 62 patients and identified recursive partitioning analysis (RPA) I class (relative risk [RR]: 7.45; 95% confidence interval [CI]:2.27-24.41) and the lack of extracerebral metastases (RR: 1.90; 95% CI: 1.09–3.29) as the two most useful independent prognostic factors indicating overall survival for patients with TCC brain metastases.[ 26 ]

Table 3

Primary cancer treatment, time interval from primary cancer diagnosis to cerebral metastasis presentation, and metastasis treatment from transitional cell carcinoma of the urinary bladder

The brain is postulated to act as a sanctuary site for metastatic tumor cells, since they are partially protected from systemic drugs by the blood–brain barrier (BBB) and blood–tumor barrier.[ 65 ] It is then possible to understand why tumors that had rarely been known to spread to the brain previously are now more frequently acting as the first sign of secondary recurrence in patients treated with novel chemotherapy regimens. To further this point, Dhote et al. noted that brain metastases normally occur late in the natural course of advanced urinary bladder cancer, and the inability of the MVAC chemotherapy regimen (methotrexate, vinblastine, adriamycin/doxorubicin, cisplatin) to cross the BBB allows for systemic control of the disease, but leaves late metastatic foci in the inaccessible brain.[ 21 ] Thus, MVAC may increase the risk of metastatic disease in patients with prolonged remission.

Neurosurgeons may expect to see more cases of brain metastases from unusual sources as a result of increased survival rates from newer, more effective systemic chemotherapy regimens. With respect to the oncologic treatment of primary TCC, the MVAC chemotherapy regimen has conferred a survival advantage over the traditional single-agent cisplatin, reducing response rates, increasing duration of remission, and improving overall survival in patients with urinary bladder cancer.[ 54 ] In 1989, Sternberg et al. reported 121 patients with advanced TCC who were treated with the MVAC chemotherapy regimen. Nineteen of the 121 patients (16%) developed brain metastases.[ 91 ] Another 1998 study by Dhote et al. reviewed 50 patients with advanced TCC treated with the MVAC chemotherapy regimen and reported eight cases (16%) of intracranial metastases.[ 21 ] These data suggest that the advent of more effective chemotherapy regimens has increased the incidence of brain metastases as secondary recurrences in patients with controlled primary or systemic urinary bladder cancer, since patients who achieve local and systemic control of their cancer may be living long enough to develop cerebral metastasis.

We report a case involving subtotal resection of a solitary cerebral TCC metastasis along the motor cortex of a 68-year-old female patient with a history of urinary bladder cancer 14 years prior. To the best of our knowledge, this case represents the first patient reported to develop isolated brain parenchyma relapse after treatment with gemcitibine for primary urinary bladder cancer, and the longest time interval between primary urinary bladder cancer diagnosis and development of TCC brain metastasis. The high metastatic potential of TCC of the urinary bladder is exemplified by our patient, who suffered multiple recurrences in the 5 years prior to presentation with cerebral metastasis. Given the aggressive nature of this tumor, one plausible explanation for TCC cerebral metastasis is early invasion of brain parenchyma by tumor cells that remain dormant.[ 57 ] These micrometastases may then be activated at a later time, eventually forming macroscopic tumors. This process may serve as a contributing factor leading to cerebral metastasis, and is consistent with a “sanctuary effect,” providing the chemotherapeutic agents are truly impervious to the BBB.

Our case is unique, given the time span of 14 years from primary diagnosis of urinary bladder cancer in 1996 to presentation of the solitary brain lesion in 2010. The patient underwent a CT scan in 2008 that showed no evidence of brain metastases. A 1998 review of the literature for metastatic TCC presenting as a solitary brain lesion by Clatterbuck et al. reports the median time of development of brain metastases as 12 to 18 months, with a range from 2 weeks to 9 years.[ 17 ] A 66-year-old male patient reported by Steinfeld in 1987 underwent transurethral resection of the urinary bladder, cystectomy, pelvic radiation therapy, and chemotherapy treatment with cyclophosphamide and platinum before developing cerebral metastasis 10 years after diagnosis of superficial urinary bladder cancer.[ 90 ] In another case series published in 1987, Bloch reported a 51-year-old male patient who developed TCC of the urinary bladder and was treated with multiple transurethral resections and thiotepa intravesical chemotherapy, as well as nephroureterectomy. This patient developed a frontal lobe metastasis 8 years after his primary cancer diagnosis.[ 9 ] We feel that our patient's chemotherapy regimen of cisplastin with gemicitabine may have contributed to her long time interval from urinary bladder cancer diagnosis to clinical presentation of cerebral metastasis.

Gemcitabine is a deoxycytidine analogue chemotherapy agent with a broad spectrum of activity against several solid tumors, including non-small-cell lung cancer, breast and ovarian cancer, pancreatic cancer, and urinary bladder cancer.[ 94 ] Gemcitabine plus cisplatin (GC) has replaced MVAC as the standard of care for patients with locally advanced and metastatic TCC. A 2000 randomized control study demonstrated a comparable survival advantage between patients with TCC urinary bladder cancer who were treated with GC or MVAC; however, a better safety profile and tolerability was observed in the GC group.[ 98 ] It is important to note that this trial excluded patients with TCC central nervous system metastases. We are unaware of any prospective or randomized studies showing the effectiveness of GC in patients with TCC brain metastases. Interestingly, Fokas’ 2010 retrospective analysis failed to show any overall survival benefits to chemotherapy in patients treated for TCC with cerebral metastases.[ 26 ] The type of chemotherapy regimen(s) used was not reported in the study.

Gemcitabine has shown differential uptake in brain tumors in rat experiments,[ 5 ] and it has been used in combination with radiation therapy for the treatment of TCC brain metastases with favorable results.[ 70 ] Gemcitabine appears to be able to cross the BBB, ostensibly due to its low size and molecular weight, through the luminal membrane endothelial cells by the nucleoside transporter, ENT1.[ 93 ] Treatment with GC for TCC of the urinary bladder may afford patients some protection against cerebral metastasis by reaching latent metastatic intracranial foci that have been otherwise unreachable, thus prolonging the time interval in which patients present with cerebral metastatic disease.

In light of the increasing incidences in brain metastases due to advances in chemotherapy potency, there may be a role in screening neuroimaging to detect asymptomatic brain metastases, but there is currently inconclusive evidence to support such efforts. Finally, the prudent surgeon should include intracranial TCC metastases in the differential diagnosis of patients presenting with neurologic symptoms and a history of primary urinary bladder cancer.

CONCLUSION

Brain metastases may present several years later in patients with TCC of the urinary bladder who have been treated with surgery and chemotherapy. Chemotherapeutic agents that penetrate the BBB, such as gemcitabine, may delay development of cerebral metastasis from primary TCC of the urinary bladder.

ACKNOWLEDGMENTS

We are grateful to Laurie A. Mena, M.S. for her helpful comments in the preparation of this manuscript.

References

1. Anderson RS, El-Mahdi AM, Kuban DA, Higgins EM. Brain metastases from transitional cell carcinoma of urinary bladder. Urology. 1992. 39: 17-20

2. Anderson TS, Regine WF, Kryscio R, Patchell RA. Neurologic complications of bladder carcinoma. Cancer. 2003. 97: 2267-72

3. Angulo JC, Lopez JI, Larrinaga JR, Flores N. Metastasising carcinoma of the urinary bladder presenting as a retro-orbital mess. Case report. Scand J Urol Nephrol. 1991. 25: 83-4

4. Angulo JC, Lopez JI, Unda-Urzaiz M, Flores N. Urinary bladder carcinoma initially manifested as brain metastases. Postgrad Med J. 1992. 68: 150-1

5. Apparaju SK, Gudelsky GA, Desai PB. Pharmacokinetics of gemcitabine in tumor and non-tumor extracellular fluid of brain: An in vivo assessment in rats employing intracerebral microdialysis. Cancer Chemother Pharmacol. 2008. 61: 223-9

6. Atta HR. Presumed metastatic transitional cell carcinoma of the choriods. Br J Opthalmol. 1983. 67: 830-3

7. Babaian RJ, Johnson DE, Llamas L, Ayala AG. Metastases from transitional cell carcinoma of urinary bladder. Urology. 1980. 16: 142-4

8. Bishop JR, Moul JW, Maldonado L, McLeod DG. Transitional cell carcinomatous meningitis after M-VAC chemotherapy. Urology. 1990. 36: 373-7

9. Bloch JL, Nieh PT, Walzak MP. Brain metastases from transitional cell carcinoma. J Urol. 1987. 137: 97-9

10. Boukriche Y, Bouccara D, Cyna-Gorse F, Dehais C, Felce-Dachez M, Masson C. Sudden bilateral hearing loss disclosing meningeal carcinomatosis. Rev Neurol (Paris). 2002. 158: 728-30

11. Bowen CD, Burton GV, Bargen RC, Madonia P, Zhang S, Toledo EG. Carcinomatous meningitis secondary to transitional cell bladder cancer. South Med J. 2010. 103: 809-12

12. Bruna J, Rojas-Marcos I, Martinez-Yelamos S, Catala I, Vidaller A, Galan C. Meningeal carcinomatosis as the first manifestation of a transitional cell carcinoma of the bladder. J Neurooncol. 2003. 63: 63-7

13. Butchart C, Dahle-Smith A, Bissett D, Mackenzie JM, Williams DJ. Isolated meningeal recurrence of transitional cell carcinoma of the bladder. Case Rep Oncol. 2010. 3: 171-5

14. Carrero Lopez VM, Caballero J, De le Rosa F, Calahorra L, Vazquez S, Garcia Luzon A. Cerebral metastasis at first manifestation of a bladder carcinoma. Actas Urol Esp. 1994. 18: 906-10

15. Chua WC, Martin PA, Kourt G. Orbital metastasis from transitional cell carcinoma of the bladder. Clin Experiment Opthalmol. 2004. 32: 447-9

16. Cieplinski W, Ciesielski TE, Haine C, Nieh P. Choroid metastases from transitional cell carcinoma of the bladder: A case report and review of the literature. Cancer. 1982. 50: 1596-600

17. Clatterbuck RE, Sampath P, Olivi A. Transitional cell carcinoma presenting as a solitary brain lesion: A case report and review of the world literature. J Neurooncol. 1998. 39: 91-4

18. Cozzarini C, Reni M, Mangili F, Baldoli MC, Galli L, Bolognesi A. Meningeal carinomatosis from transitional cell carcinoma of the bladder: Report of two cases and review of the literature. Cancer Invest. 1999. 17: 402-7

19. Davies BJ, Bastacky S, Chung SY. Large cerebellar lesion as original manifestation of transitional cell carcinoma of the bladder. Urology. 2003. 62: 749-

20. Davis RP, Spigelman MK, Zappulla RA, Sacher M, Strauchen JA. Isolated central nervous system metastasis from transitional cell carcinoma of the bladder: Report of a case and review of the literature. Neurosurgery. 1986. 18: 622-4

21. Dhote R, Beuzeboc P, Thiounn N, Flam T, Zerbib M, Christoforov B. High incidence of brain metastases in patients treated with an M-VAC regimen for advanced bladder cancer. Eur Urol. 1998. 33: 392-5

22. D’Souza N, Khan MJ, Robinson S, Motiwala H. A rare and unusual case of isolated cerebellar metastasis from a non-muscle invasive transitional cell carcinoma of bladder. JRSM Short Rep. 2011. 2: 50-

23. Eng C, Cunningham D, Quade BJ, Schwamm L, Kantoff PW, Skarin AT. Meningeal carcinomatosis from transitional cell carcinoma of the bladder. Cancer. 1993. 72: 553-7

24. Felip E, Rovirosa MA, Salud A, Capdevila F, Bellmunt J, Giralt J. Orbital metastases from transitional-cell cancer of the urinary bladder. Urol Int. 1991. 46: 82-4

25. Fierlbeck I, Helmbold P. Bilateral periorbital metastases of transitional cell carcinoma of the bladder. Hautarzt. 2011. 62: 287-9

26. Fokas E, Henzel M, Engenhart-Cabillic R. A comparison of radiotherapy with radiotherapy plus surgery for brain metastases from urinary bladder cancer: Analysis of 62 patients. Strahlenther Onkol. 2010. 186: 565-71

27. Fynn-Thompson N, McKiernan JM, Fay A. Transitional cell carcinoma of the urinary bladder metastatic to the orbit. Opthal Plast Reconstr Surg. 2003. 19: 165-7

28. Germiyanoglu C, Horasanli K, Erol D, Altug U, Peskircioglu L. A case of transitional cell carcinoma of the bladder presenting with brain metastases. Int Urol Nephrol. 1993. 25: 345-9

29. Girgis S, Ramzy I, Baer SC, Schwartz MR. Fine needle aspiration diagnosis of transitional cell carcinoma metastatic to the brain: A case report. Acta Cytol. 1999. 43: 235-8

30. Goldman SM, Fajardo AA, Naraval R, Madewell JE. Metastatic transitional cell carcinoma from the bladder: Radiographic manifestations. AJR Am J Roentgenol. 1979. 132: 419-25

31. Goodman OB, Milowsky MI, Kaplan J, Hussain M, Nanus DM. Carcinomatous meningitis in a patient with Her2/neu expressing bladder cancer following trastuzumab and chemotherapy: A case report and review of the literature. J Med Case Rep. 2009. 3: 9110-

32. Gordon HL, Munro R. Ocular metastasis of bladder cancer. South Med J. 1974. 67: 745-6

33. Graf A, Buchberger W, Langmayr H, Schmid KW. Site preference of metastatic tumours of the brain. Virchows Arch A Pathol Anat Histopathol. 1988. 412: 493-8

34. Haberland C.editorsClinical neuropathology. New York, NY: Demos Medical Publishing; 2007. p. 246-

35. Hamaguchi T, Hamami G, Kamidono S, Umezu K, Nakamura A, Watanabe M. A case of bladder tumor with brain metastasis. Hinyokika Kiyo. 1986. 32: 1524-6

36. Hara Y, Kobayashi Y, Goto K, Tozuka K, Tokue A, Mochizuki M. A case of carcinomatous meningitis from transitional cell carcinoma of the urinary bladder. Hinyokika Kiyo. 1994. 40: 1113-7

37. Hasbini A, Himberlin C, Beguit I, Bonnet-Gausserand F, Coninx P. Carcinomatous meningitis: Rare complication of bladder cancer. Rev Med Interne. 1997. 18: 402-6

38. Hugkulstone CE, Winder S, Sokal M. Bilateral orbital metastases from transitional cell carcinoma of the bladder. Eye (Lond). 1995. 9: 664-6

39. Hussein AM, Savaraj N, Feun LG, Ganjei P, Donnelly E. Carcinomatous meningitis from transitional cell carcinoma of the bladder: Case report. J Neurooncol. 1989. 7: 255-60

40. Hust MH, Pfitzer P. Cerebrospinal fluid and metastasis of transitional cell carcinoma of the bladder. Acta Cytol. 1982. 26: 217-23

41. Iriarte Loizaga A, Garcia Arciniega JM, Riano Infante R, Jaime Ullate V, Sastre Garcia E, Corral Flores N. Carcinomatosis meningea en un tumor vesical. Actas Urol Esp. 1999. 23: 873-5

42. Jankevicius F, Sruogis A, Ulys A, Zykus A, Sumauskas R. Prolonged remission in a patient with transitional cell carcinoma of the bladder developing brain metastases after systemic chemotherapy: A case report. Tumori. 2004. 90: 420-1

43. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009. 59: 225-49

44. Juan Vidal O, de Paz Arias L, Catala Barcelo J, Garcia Escrig M. Meningeal carcinomatosis as first manifestation of carcinoma of the bladder: Report of 2 cases. An Med Interna. 2000. 17: 425-8

45. Kabalin JN, Freiha FS, Torti FM. Brain metastases from transitional cell carcinoma of the bladder. J Urol. 1988. 140: 820-4

46. Kattan J, Droz JP, Boutan-Laroze A, Deforges B, Terrier-Lacombe MJ, Vanel D. Choroid metastasis in a case of urothelial carcinoma metastatic from the bladder. Prog Urol. 1991. 1: 466-9

47. Kim P, Ashton D, Pollard JD. Isolated hypoglycorrachia: Leptominingeal carcinomatosis causing subacute confusion. J Clin Neurosci. 2005. 12: 841-3

48. Kishi K, Hirota T, Matsumoto K, Kakizoe T, Murase T, Fujita J. Carcinoma of the bladder: A clinical and pathological analysis of 87 autopsy cases. J Urol. 1981. 125: 36-9

49. Klos KJ, O’neil BP. Brain metastases. Neurologist. 2004. 10: 31-46

50. Kobayashi T, Ogura K, Nishizawa K, Ono M, Ueno Y, Miyake H. Clinically isolated cerebellar metastasis of renal pelvic urothelial cancer. Int J Urol. 2004. 11: 47-9

51. Krauss HR, Slamovits TL, Sibony PA, Dekker A, Kennerdell JS. Orbital metastasis of bladder carcinoma. Am J Opthalmol. 1982. 94: 265-7

52. Larson D, Rubinstein J, McDermott M, De Vita VT, Lawrence TS, Rosenberg SA.editors. Treatment of metastatic cancer. Cancer principles and practice of oncology. Philadelphia: Lippincott Williams & Wilkins; 2004. p. 2323-98

53. Lin HC, Chang CH, Li WM, Hsiao HL, Chang TH, Wu WJ. Orbital metastasis from urothelial carcinoma of the urinary bladder. Kaohsiung J Med Sci. 2007. 23: 84-8

54. Loehrer PJ, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I. A random comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: A cooperative group study. J Clin Oncol. 1992. 10: 1066-73

55. Loizaga A, Arciniega J, Infante R, Ullate V, Garcia E, Flores N. Carcinomatosis Meningea en un tumor vesical. Actas Urol Esp. 1999. 23: 873-5

56. Lower WE, Watkins RM. A case of primary carcinoma of the bladder with metastasis to the brain. Am J Med Sci. 1924. 167: 434-

57. Luzzi KJ, MacDonald IC, Schmidt EE, Kerkvliet N, Morris VL, Chambers AF. Multistep nature of metastatic inefficiency: Dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol. 1998. 153: 865-73

58. Mahmoud-Ahmed AS, Suh JH, Kupelian PA, Klein EA, Peereboom DM, Dreicer R. Brain metastases from bladder carcinoma: Presentation, treatment and survival. J Urol. 2002. 167: 2419-22

59. Mandell S, Wernz J, Morales P, Weinberg H, Steinfeld A. Carcinometous meningitis from transitional cell carcinoma of bladder. Urology. 1985. 25: 520-1

60. Matsushita M, Kawasaki Y, Okada Y. Carcinomatous meningitis from urothelial carcinoma of bladder and ureter: Case report. Nihon Hinyokika Gakkai Zasshi. 2004. 95: 817-9

61. Moes G, Vogel H.editors. Metastatic neoplasms of the central nervous system. In: Nervous system (Cambridge Illustrated Surgical Pathology). New York: Cambridge University Press; 2009. p. 309-

62. Moon K, Jung S, Lee K, Hwang EU, Kim I. Intracranial metastasis from primary transitional cell carcinoma of female urethra: Case report & review of the literature. BMC Cancer. 2011. 11: 23-

63. Nabi G, Dadeya S, Dogra PN, Lal H. Eye metastasis from urothelial tumours. Int Urol Nephrol. 2002. 34: 51-4

64. Nakagawa S, Nakao M, Toyoda K, Nukui M, Takada H, Ebisui K. Complete remission of brain metastasis of bladder cancer treated by M-VAC therapy. Hinyokika Kiyo. 1989. 35: 333-5

65. Palmieri D, Chambers AF, Felding-Habermann B, Huang S, Steeg PS. The biology of metastasis to a sanctuary site. Clin Cancer Res. 2007. 13: 1656-62

66. Pe’er J, Zimmerman LE. Ocular metastases from transitional cell carcinoma of the urinary tract. Graefes Arch Clin Exp Ophthalmol. 1984. 221: 137-41

67. Perlmutter AE, Zaitoon A, Sparks SS, Zaslau S, Zaitoon M. Isolated cerebellar metastasis in a patient with organ-confined, lymph node negative bladder cancer. W V Med J. 2006. 102: 14-5

68. Posner J. Management of central nervous system metastases. Semin Oncol. 1977. 4: 81-91

69. Prats J, Bellmunt J, Calvo MA, Sarrias F, Toran N. Orbital metastasis, by transitional cell carcinoma of the bladder. Int Urol Nephrol. 1989. 21: 389-92

70. Protzel C, Zimmermann , Asse E, Kallwellis G, Klebingat KJ. Gemcitabine and radiotherapy in the treatment of brain metastases from transitional cell carcinoma of the bladder: A case report. J Neurooncol. 2002. 57: 141-5

71. Quinn CM, Thomas H, Prentice MB. Urinary bladder carcinoma initially manifested as brain metastases. Postgrad Med J. 1992. 68: 689-91

72. Rades D, Meyners T, Veninga T, Stalpers LJ, Schild SE. Hypofractionated whole-brain radiotherapy for multiple brain metastases from transitional cell carcinoma of the bladder. Int J Radiat Oncol Biol Phys. 2010. 78: 404-8

73. Raghavan D, Chye RW. Treatment of carcinomatous meningitis from transitional cell carcinoma of the bladder. Br J Urol. 1991. 67: 438-40

74. Rastogi R, Singh AK, Rastogi UC, Mohan C, Rastogi V. Neurological deficit as the first manifestation of vesical transitional cell carcinoma. Saudi J Kidney Dis Transpl. 2011. 22: 1022-5

75. Remon J, Guardeno R, Badia A, Cardona T, Picaza JM, Lianes P. Blindness in a bladder cancer patient. Clin Transl Oncol. 2007. 9: 117-8

76. Resnick MI, O’Conor VJ, Grayhack JT. Metastases to the eye from transitional cell carcinoma of the bladder. J Urol. 1975. 114: 722-4

77. Rosenstein M, Wallner K, Scher H, Sternberg CN. Treatment of brain metastases from bladder cancer. J Urol. 1993. 149: 480-3

78. Sakuma S, Nakagawa Y, Imamura H, Takeda M, Isobe M, Ishii N. A very rare autopsy of metastatic brain tumor originating from uretheral cancer. No Shinkei Geka. 1989. 17: 883-6

79. Salvati M, Cervoni L, Orlando ER, Delfini R. Solitary brain metastases from carcinoma of the bladder. J Neurooncol. 1993. 16: 217-20

80. Santarossa S, Vaccher E, Balestreri L, Volpe R, Tirelli U. Solitary meningeal recurrence in a patient with transitional cell carcinoma of the bladder with locally bulky disease at presentation. J Neurooncol. 1997. 35: 141-3

81. Scott JA, Williams R. Transitional cell carcinoma of the bladder metastatic to the orbit. Eye (Lond). 1995. 9: 664-6

82. Shamdas GJ, McLaren GD, Grimm T, Everson LK. Solitary cerebellar metastasis from transitional cell carcinoma of bladder. Urology. 1992. 40: 50-3

83. Shikishima K, Miyake A, Ikemoto I, Kawakami M. Metastasis to the orbit from transitional cell carcinoma of the bladder. Jpn J Ophthalmol. 2006. 50: 469-73

84. Shinagare AB, Ramaiya NH, Jagannathan JP, Fennessy FM, Taplin ME, Van den Abbeele AD. Metastatic Pattern of bladder cancer: Correlation with the characteristics of the primary tumor. AJR Am J Roentgenol. 2011. 196: 117-22

85. Smiley SS. An orbital metastasis from the urinary bladder. Arch Ophthalmol. 1965. 74: 809-10

86. Soffietti R, Ruda R, Mutani R. Management of brain metastases. J Neurol. 2002. 249: 1357-69

87. Souza Filho JP, Odashiro AN, Pereira PR, Al-Buloushi A, Codere F, Burnier MN. Orbital metastasis of urinary bladder carcinoma: A clinicopathologic report and review of literature. Orbit. 2005. 24: 269-71

88. Steg RE, Frank AR, Lefkowitz DM. Complex partial status epilepticus in a patient with dural metastases. Neurology. 1993. 43: 2389-92

89. Last Accessed 2011 Aug 17. Available from: http://emedicine.medscape.com/article/438262-overview .

90. Steinfeld AD, Zelefsky M. Brain metastases from carcinoma of bladder. Urology. 1987. 29: 375-6

91. Sternberg CN, Yagoda A, Scher HI, Watson RC, Geller N, Herr HW. Methotrexate, vinblastine, doxorubicin and cisplatin for advanced transitional cell carcinoma of the urothelium. Cancer. 1989. 64: 2448-58

92. Tadepalli S, Coleman T, Hacket LA, Liles GB. Carcinomatous meningitis: The natural history of successfully treated metastatic bladder cancer. Case Rep Oncol. 2011. 4: 406-12

93. Thomas FC, Rudraraju V, Taskar K, Lockman PR, Palmieri D, Steeg P.editors. Brain uptake of gemcitabine across the blood-brain barrier. AAPS Annual Meeting & Exposition. Atlanta, Georgia: 2008. p.

94. Toschi L, Finocchiaro G, Bartolini S, Giola V, Cappuzzo F. Role of gemcitabine in cancer therapy. Future Oncol. 2005. 1: 7-17

95. Turgut M, Akyuz O, Kacar F. Solitary cerebral metastasis from transitional cell carcinoma of the urinary tract. J Clin Neurosci. 2007. 14: 1129-32

96. Uncu D, Arpaci F, Beyzadeoglu M, Gunal A, Surenkok S, Ozturk M. Meningeal carcinomatosis: An extremely rare involvement of urinary bladder carcinoma. Tumori. 2010. 96: 352-4

97. Vinchon M, Ruchoux MM, Sueur JP, Assaker R, Christiaens JL. Solitary brain metastasis as only recurrence of a carcinoma of the bladder. Clin Neuropathol. 1994. 13: 338-40

98. von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: Results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000. 18: 3068-77

99. Wakisaka S, Miyahara S, Nonaka A, Asami N, Kinoshita K, Kohriyama K. Brain metastasis from transitional cell carcinoma of the bladder. Neurol Med Chir (Tokyo). 1990. 30: 188-90

100. Walker MT, Kapoor V, Raizer JJ, Abrey LE.editors. Neuroimaging of parenchymal brain metastases. Brain metastasis. New York: Springer; 2007. p. 31-2

101. Wang J, Ngan S, Dina R, Strickland N, Waxman J. A very unusual presentation of metastatic transitional cell carcinoma of the bladder. Curr Urol. 2007. 1: 50-2

102. Wettach GR, Steele EA. Urothelial cell carcinoma of the bladder presenting as orbital metastasis. Arch Pathol Lab Med. 2008. 132: 1224-

103. Yumura Y, Chiba K, Okada Y, Hirokawa M. Brain metastasis of bladder carcinoma after total cystectomy: A case report. Hinyokika Kiyo. 2000. 46: 807-9

104. Zennami K, Yamada Y, Nakamura K, Aoki S, Taki T, Honda N. Solitary brain metastasis from pT1, G3 bladder cancer. Int J Urol. 2008. 15: 96-8

105. Zigouris A, Pahatouridis D, Mihos E, Alexiou GA, Nesseris J, Zikou AK. Solitary cystic cerebral metastasis from transitional cell carcinoma of the bladder. Acta Neurol Belg. 2009. 109: 322-5

106. Zwicker F, Herfarth K, Debus J. Palliative radiotherapy for a retrobulbar metastasis from a urinary bladder carcinoma. Ophthalmologe. 2008. 105: 170-2