SOLITARY CEREBELLAR METASTASIS FROM TRANSITIONAL CELL CARCINOMA OF BLADDER GLENN J, SHAMDAS, M.D. GORDON D. McLAREN, M.D. TERRENCE GRIMM, M.D. LLOYD K. EVERSON, M.D. From the Departments of Internal Medicine and Pathology, University of North Dakota School of Medicine, Fargo Clinic, and Veterans Affairs Medical Center, Fargo, North Dakota ABSTRACT-Brain metastasisfkom transitional cell carcinoma of the bladder is unusual, occurring most often in the presence of widespread systemic metas@es. We report on a patient who presented with an isolated cerebellar metastasis and recurrent carcinoma of the bladder, after treatment with local excision and intravesical thiotepa. Further evaluation failed to demonstrate other distant metastases. Excision of the cerebellar lesion revealed transitional cell carcinema identical to the original bladder tumor In a review of the literature, we found reports of two similar patients in whom a solitary CeTebellaT lesion was the first sign of metastasis from carcinoma of the bladder; neither patient had evidence of other distant metastases, and neither previozrsly had received systemic chemotherapy. These observations indicate that central nervous system metastasis fTom carcinoma of the bladder, while Tare, should be considered in the differential diagnosis of solitary intTw?Tt?bdaT ksions in such patients. Systemic metastases occur frequently in patients with transitional cell carcinoma of the bladder, but central nervous system (CNS) involvement is relatively uncommon. In several large autopsy series, the incidence of brain metastasis ranged from 0 to 8.3 percent.‘“’ In most cases, there were either multiple CNS metastases or other distant metastases.ep”7However, a few cases have presented with solitary metastases to the cerebral hemispheres, without evidence of recurrent or disseminated disease.6~8~e In addition, 4 patients have been described in whom an isolated metastatic lesion was identified in the cerebellum.e~lo~lrTwo of these patients had no other distant metastases and had received only local therapy.e*loHerein we report on a patient with a solitary cerebellar metastasis from transitional cell carcinoma in association with recurrent tumor in the bladder. As in earlier reports, the patient had no evidence of other distant metastases and had not received systemic chemotherapye*ro
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A number of recent reports have drawn attention to an apparent increase in the incidence of CNS metastases from transitional cell carcinoma among patients treated with effective systemic combination chemotherapy for advanced disease.5~e**,11-13 However, our observations and those of otherse*rO indicate that a solitary cerebellar lesion can be the first manifestation of metastatic spread from bladder carcinoma and can occur in patients who previously have not received systemic chemotherapy. Case Report An eighty-four-year-old woman first sought medical attention at another hospital for a three-month history of progressive unsteadiness of gait and acute onset of occipital headaches seven days earlier. A computerized tomographic (CT) brain scan demonstrated a large cerebellar mass, and she was referred to our institution for further evaluation. Five months UROLOGY
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FIGURE 2. Photomicrograph showing transitional cell carcinoma me&static to cerebellum; moderately dijjerentiated transitional epithelial cells with necrosis and inflammation on left, with normal cerebellum opposite (hematoxylin and eosin, original magnijication x 110).
Contrast-enhanced CT scan showing right cerebellar mass lesion (arrowheads).
FIGURE 1.
earlier, gross hematuria had developed. Cystoscopy at that time revealed a lesion involving the right side of the dome of the bladder, which a biopsy specimen proved to be transitional cell carcinoma. A transurethral resection of the involved portion of the bladder was performed, and pathologic examination showed a grade II papillary transitional cell carcinoma with invasion of the smooth muscle wall. Subsequently, the patient received local chemotherapy with bladder instillations of thiotepa, 60 mg per week, for six weeks. Neurologic examination revealed mild impairment of recent memory and horizontal nystagmus. The ability to perform finger-to-nose and heel-to-knee tests was impaired on the right side, and gait was ataxic. A CT scan of the brain with contrast medium demonstrated a 4.5 x 4 cm, irregular enhancing mass lesion in the right cerebellar hemisphere, with surrounding edema and a shift of the fourth ventricle to the left (Fig. 1). A cerebral angiogram showed diffuse atherosclerotic changes, vascular displacement, and some mass effect produced by a right cerebellar avascular lesion. Examination of the urinary sediment showed microscopic hematuria. Cystoscopy revealed a 1.5-cm area of erythema, suggestive of recurrent tumor, in the dome of the bladder on the
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i JULY1992 I VOLUME40,NUMBERl
right. Urine cytology demonstrated the presence of malignant transitional epithelial cells. Liver function tests, a chest roentgenogram, and bone scan were normal. A CT scan of the abdomen and pelvis showed no evidence of metastatic disease. The patient was treated initially with dexamethasone 4 mg intravenously every six hours. On hospital day 4, a right suboccipital craniotomy was performed, with removal of the portion of the right superolateral cerebellum containing the tumor. Histologic examination of the specimen revealed a moderately differentiated transitional cell carcinoma that was morphologically identical to the original bladder neoplasm (Fig. 2). The margins were noted to be free of tumor. Postoperatively external beam radiation (3,600 rad) was administered to the whole brain in 10 fractions over the next two weeks. The dose of dexamethasone was gradually tapered, and at the time of discharge the patient’s ataxia had begun to improve. Comment Carcinoma of the bladder is the sixth most common malignancy in the United States7 Although early reports suggested that systemic metastases occur in only 5 to 15 percent of patients,14 more recent studies indicate frequencies ranging from 30 to 70 percent.1.3 The most common sites of metastasis are the pelvic lymph
51
nodes (37-78 %), liver (29-38 %), lung (2936 % ), and bones (24-27 % ) . I.3 CNS involvement is thought to be relatively uncommon.1-4 Kishi et al. ,3 found no example of CNS metastasis among 87 autopsy cases of bladder cancer, 77 of which were transitional cell carcinoma. In other series, the reported incidence has ranged from less than 1 percent4 to as high as 6-8 percent,1’2 with most cases involving metastases to the cerebral hemispheres. Metastases to the cerebellum, on the other hand, appear to be rare. In a review of cases no bladder carcinoma was identified among 59 patients with cerebellar metastases from a variety of primary sites.15 The first case of a solitary cerebellar metastasis from bladder carcinoma was reported by McKay in 1930. lo Neurologic symptoms developed and the patient died twenty-one months after the initial diagnosis of bladder cancer. Postmortem examination revealed transitional cell carcinoma of the bladder with an isolated metastasis in the cerebellum, but no evidence of other systemic metastases. More recently, Steinfeld and Zelefskyli reported a similar case, although the patient presented initially with other systemic metastases. Kabalin, Freiha, and Torti described 2 additional patients in whom a cerebellar lesion was the first sign of recurrence. One of these 2 patients had undergone cystectomy only, while the other had received radiotherapy and systemic chemotherapy for locally invasive tumor, followed by cystectomy. In the patient reported herein, a solitary cerebellar lesion was the first manifestation of distant metastasis from bladder carcinoma. The patient had cystoscopic and cytologic findings consistent with local recurrence of the primary tumor, but had no evidence of other distant metastases and had not received systemic chemotherapy. It has been suggested that abdominal and pelvic neoplasms may have a propensity for metastasis to the cerebellum,15 possibly as a result of retrograde dissemination through the vertebral venous system via Batson’s plexus, bypassing the lung, and terminating in the intracranial venous sinuses at the foramen magnum. m’ Such a mechanism may explain the finding of cerebellar metastasis, despite the absence of other systemic metastases, in our patient and others reported previously.eJO A recent increase in reports of CNS metastases from transitional cell carcinoma of the bladder5,8,8J1J3 has raised the question of whether this apparent alteration in the recur-
52
rence pattern of bladder carcinoma may be related to newer, more aggressive approaches to high-grade tumors with combined therapy, including irradiation, radical surgery, and cisplatin-based systemic combination chemotherapy.e A possible explanation for such a phenomenon is that the CNS may act as a sanctuary for residual tumor due to poor penetration of the blood-brain barrier by chemotherapeutic agents. Thus, with better control of systemic disease and improved survival, CNS metastases as a late complication may become more common. Our patient, however, as well as 2 of the 4 other reported cases of solitary cerebellar metastases from bladder carcinoma,OJO had not received previous systemic combination chemotherapy. Other observers have reported similar findings in patients with metastases to the cerebral hemispheres, which also can be the first site of systemic spread of disease in such patients. For example, in 1924 Lower and Watkin# reported on a patient with bladder carcinoma and an isolated intracerebral metastasis, but no other metastatic disease. More recently, 2 similar cases have been described,sJ1 although in one there was residual disease due to unresectability of the primary bladder tumor.” In all 3 cases, however, there was no history of previous systemic combination chemotherapy. These observations indicate that, although the incidence of CNS metastases may have increased due to better control of systemic disease with chemotherapy, metastasis to the brain from bladder carcinoma can be the first manifestation of systemic spread in patients who have not received such treatment. Patients with cerebellar metastases often complain of occipital and/or frontal headaches and gait disturbances. l5 In our patient, the cerebellar metastasis was detected by brain CT scan, and this approach usually is adequate for diagnosis. Magnetic resonance imaging is more sensitive, however, and should be considered if the initial CT scan is negative.15 In the absence of other systemic metastases, patients with solitary CNS metastases from bladder carcinoma may benefit from surgical resection, as illustrated by our patient and others.eJ External beam irradiation may be a beneficial adjunctive form of therapy in this situation and may offer effective palliation for patients with progressive systemic disease or multiple CNS metastases. Whether or not patients with highgrade tumors should receive prophylactic brain
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/ JULY 1992
/
VOLUME
40, NUMBER
1
irradiation in conjunction with systemic combination chemotherapy at an early stage of the disease is a question that requires further study. Our patient and others reported in the literaturew-1 1 emphasize the fact that CNS metastases from transitional cell carcinoma of the bladder may occur without evidence of widespread metastatic disease. These lesions may be solitary and may involve either the cerebral hemispheres8J’J1 or the cerebellum, as described in the current report and previously by others.sJo Thus, a solitary CNS metastasis should be considered in the differential diagnosis of patients with carcinoma of the bladder in whom neurologic symptoms develop, even in the absence of other systemic metastases. Arizona Cancer Center 1501 North Campbell Tucson, Arizona 85724 (DR. SHAMDAS) References 1. Babaian RJ, et al: Metastases from transitional cell carcinoma of urinary bladder, Urology 16: 142 (1980). 2. Hust MH, and Pfitzer P: Cerebrospinal fluid and me&stases of transitional cell carcinoma of the bladder, Acta Cytol 26: 217 (1982).
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3. Kishi K, et al: Carcinoma of the bladder: a clinical and pathological analysis of 87 autopsy cases, J Urol 125: 36 (1981). 4. Whitmore WF Jr, et al: Radical cystectomy with or without prior irradiation in the treatment of bladder cancer, J Urol 118: 184 (1977). 5. Bloch JL, Nieh PT, and Walzak MP: Brain metastases from transitional cell carcinoma, J Urol 137: 97 (1987). 6. Kabalin J, Freiha FS, and Torti FM: Brain metastases from transitional cell carcinoma of the bladder, J Urol 140: 820 (1988). 7. Page S, and Asire AJ: Cancer rates and risks, publication No. 85-691, Bethesda, National Institutes of Health, 1985. 8. Davis RP, et al: Isolated central nervous system metastasis from transitional cell carcinoma of the bladder: report of a case and review of the literature, Neurosurgery 18: 622 (1986). 9. Lower WE, and Watkins RM: Case of primary carcinoma of the bladder with metastasis to the brain, Am J Med Sci 167: 434 (1924). lO.McKay HW: Solitary metastasis to the brain from carcinoma of the bladder, Br J Urol 2: 156 (1930). 11. Steinfeld AD, and Zelefsky M: Brain metastases from carcinoma of bladder, Urology 29: 375 (1987). 12. Kies M: Editorial comment: Kabalin JN, et al: Brain metastasis from transitional cell carcinoma of the bladder, J Urol 140: 824 (1988). 13. Mandell S, et cd: Carcinomatous meningitis from transitional cell carcinoma of the bladder, Urology 25: 520 (1985). 14. Fetter TR, et cd: Carcinoma of the bladder: sites of metastases, J Urol 81: 746 (1959). 15. Fadul C, Misulis KE, and Wiley RG: Cerebellar metastases: diagnostic and management considerations, J Clin Oncol5: 1107 (1987). 16. Batson OV: The function of the vertebral veins and their role in the spread of metastases, Ann Surg 112: 138 (1940). 17. Castaldo JE, et al: Intracranial metastases due to prostatic carcinoma, Cancer 52: 1739 (1983).
53
50
A number of recent reports have drawn attention to an apparent increase in the incidence of CNS metastases from transitional cell carcinoma among patients treated with effective systemic combination chemotherapy for advanced disease.5~e**,11-13 However, our observations and those of otherse*rO indicate that a solitary cerebellar lesion can be the first manifestation of metastatic spread from bladder carcinoma and can occur in patients who previously have not received systemic chemotherapy. Case Report An eighty-four-year-old woman first sought medical attention at another hospital for a three-month history of progressive unsteadiness of gait and acute onset of occipital headaches seven days earlier. A computerized tomographic (CT) brain scan demonstrated a large cerebellar mass, and she was referred to our institution for further evaluation. Five months UROLOGY
/ JULY 1992 I
VOLUME 40,NUMBER 1
FIGURE 2. Photomicrograph showing transitional cell carcinoma me&static to cerebellum; moderately dijjerentiated transitional epithelial cells with necrosis and inflammation on left, with normal cerebellum opposite (hematoxylin and eosin, original magnijication x 110).
Contrast-enhanced CT scan showing right cerebellar mass lesion (arrowheads).
FIGURE 1.
earlier, gross hematuria had developed. Cystoscopy at that time revealed a lesion involving the right side of the dome of the bladder, which a biopsy specimen proved to be transitional cell carcinoma. A transurethral resection of the involved portion of the bladder was performed, and pathologic examination showed a grade II papillary transitional cell carcinoma with invasion of the smooth muscle wall. Subsequently, the patient received local chemotherapy with bladder instillations of thiotepa, 60 mg per week, for six weeks. Neurologic examination revealed mild impairment of recent memory and horizontal nystagmus. The ability to perform finger-to-nose and heel-to-knee tests was impaired on the right side, and gait was ataxic. A CT scan of the brain with contrast medium demonstrated a 4.5 x 4 cm, irregular enhancing mass lesion in the right cerebellar hemisphere, with surrounding edema and a shift of the fourth ventricle to the left (Fig. 1). A cerebral angiogram showed diffuse atherosclerotic changes, vascular displacement, and some mass effect produced by a right cerebellar avascular lesion. Examination of the urinary sediment showed microscopic hematuria. Cystoscopy revealed a 1.5-cm area of erythema, suggestive of recurrent tumor, in the dome of the bladder on the
UROLOGY
i JULY1992 I VOLUME40,NUMBERl
right. Urine cytology demonstrated the presence of malignant transitional epithelial cells. Liver function tests, a chest roentgenogram, and bone scan were normal. A CT scan of the abdomen and pelvis showed no evidence of metastatic disease. The patient was treated initially with dexamethasone 4 mg intravenously every six hours. On hospital day 4, a right suboccipital craniotomy was performed, with removal of the portion of the right superolateral cerebellum containing the tumor. Histologic examination of the specimen revealed a moderately differentiated transitional cell carcinoma that was morphologically identical to the original bladder neoplasm (Fig. 2). The margins were noted to be free of tumor. Postoperatively external beam radiation (3,600 rad) was administered to the whole brain in 10 fractions over the next two weeks. The dose of dexamethasone was gradually tapered, and at the time of discharge the patient’s ataxia had begun to improve. Comment Carcinoma of the bladder is the sixth most common malignancy in the United States7 Although early reports suggested that systemic metastases occur in only 5 to 15 percent of patients,14 more recent studies indicate frequencies ranging from 30 to 70 percent.1.3 The most common sites of metastasis are the pelvic lymph
51
nodes (37-78 %), liver (29-38 %), lung (2936 % ), and bones (24-27 % ) . I.3 CNS involvement is thought to be relatively uncommon.1-4 Kishi et al. ,3 found no example of CNS metastasis among 87 autopsy cases of bladder cancer, 77 of which were transitional cell carcinoma. In other series, the reported incidence has ranged from less than 1 percent4 to as high as 6-8 percent,1’2 with most cases involving metastases to the cerebral hemispheres. Metastases to the cerebellum, on the other hand, appear to be rare. In a review of cases no bladder carcinoma was identified among 59 patients with cerebellar metastases from a variety of primary sites.15 The first case of a solitary cerebellar metastasis from bladder carcinoma was reported by McKay in 1930. lo Neurologic symptoms developed and the patient died twenty-one months after the initial diagnosis of bladder cancer. Postmortem examination revealed transitional cell carcinoma of the bladder with an isolated metastasis in the cerebellum, but no evidence of other systemic metastases. More recently, Steinfeld and Zelefskyli reported a similar case, although the patient presented initially with other systemic metastases. Kabalin, Freiha, and Torti described 2 additional patients in whom a cerebellar lesion was the first sign of recurrence. One of these 2 patients had undergone cystectomy only, while the other had received radiotherapy and systemic chemotherapy for locally invasive tumor, followed by cystectomy. In the patient reported herein, a solitary cerebellar lesion was the first manifestation of distant metastasis from bladder carcinoma. The patient had cystoscopic and cytologic findings consistent with local recurrence of the primary tumor, but had no evidence of other distant metastases and had not received systemic chemotherapy. It has been suggested that abdominal and pelvic neoplasms may have a propensity for metastasis to the cerebellum,15 possibly as a result of retrograde dissemination through the vertebral venous system via Batson’s plexus, bypassing the lung, and terminating in the intracranial venous sinuses at the foramen magnum. m’ Such a mechanism may explain the finding of cerebellar metastasis, despite the absence of other systemic metastases, in our patient and others reported previously.eJO A recent increase in reports of CNS metastases from transitional cell carcinoma of the bladder5,8,8J1J3 has raised the question of whether this apparent alteration in the recur-
52
rence pattern of bladder carcinoma may be related to newer, more aggressive approaches to high-grade tumors with combined therapy, including irradiation, radical surgery, and cisplatin-based systemic combination chemotherapy.e A possible explanation for such a phenomenon is that the CNS may act as a sanctuary for residual tumor due to poor penetration of the blood-brain barrier by chemotherapeutic agents. Thus, with better control of systemic disease and improved survival, CNS metastases as a late complication may become more common. Our patient, however, as well as 2 of the 4 other reported cases of solitary cerebellar metastases from bladder carcinoma,OJO had not received previous systemic combination chemotherapy. Other observers have reported similar findings in patients with metastases to the cerebral hemispheres, which also can be the first site of systemic spread of disease in such patients. For example, in 1924 Lower and Watkin# reported on a patient with bladder carcinoma and an isolated intracerebral metastasis, but no other metastatic disease. More recently, 2 similar cases have been described,sJ1 although in one there was residual disease due to unresectability of the primary bladder tumor.” In all 3 cases, however, there was no history of previous systemic combination chemotherapy. These observations indicate that, although the incidence of CNS metastases may have increased due to better control of systemic disease with chemotherapy, metastasis to the brain from bladder carcinoma can be the first manifestation of systemic spread in patients who have not received such treatment. Patients with cerebellar metastases often complain of occipital and/or frontal headaches and gait disturbances. l5 In our patient, the cerebellar metastasis was detected by brain CT scan, and this approach usually is adequate for diagnosis. Magnetic resonance imaging is more sensitive, however, and should be considered if the initial CT scan is negative.15 In the absence of other systemic metastases, patients with solitary CNS metastases from bladder carcinoma may benefit from surgical resection, as illustrated by our patient and others.eJ External beam irradiation may be a beneficial adjunctive form of therapy in this situation and may offer effective palliation for patients with progressive systemic disease or multiple CNS metastases. Whether or not patients with highgrade tumors should receive prophylactic brain
UROLOGY
/ JULY 1992
/
VOLUME
40, NUMBER
1
irradiation in conjunction with systemic combination chemotherapy at an early stage of the disease is a question that requires further study. Our patient and others reported in the literaturew-1 1 emphasize the fact that CNS metastases from transitional cell carcinoma of the bladder may occur without evidence of widespread metastatic disease. These lesions may be solitary and may involve either the cerebral hemispheres8J’J1 or the cerebellum, as described in the current report and previously by others.sJo Thus, a solitary CNS metastasis should be considered in the differential diagnosis of patients with carcinoma of the bladder in whom neurologic symptoms develop, even in the absence of other systemic metastases. Arizona Cancer Center 1501 North Campbell Tucson, Arizona 85724 (DR. SHAMDAS) References 1. Babaian RJ, et al: Metastases from transitional cell carcinoma of urinary bladder, Urology 16: 142 (1980). 2. Hust MH, and Pfitzer P: Cerebrospinal fluid and me&stases of transitional cell carcinoma of the bladder, Acta Cytol 26: 217 (1982).
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I JULY 1992
/ VOLUME
40, NUMBER
1
3. Kishi K, et al: Carcinoma of the bladder: a clinical and pathological analysis of 87 autopsy cases, J Urol 125: 36 (1981). 4. Whitmore WF Jr, et al: Radical cystectomy with or without prior irradiation in the treatment of bladder cancer, J Urol 118: 184 (1977). 5. Bloch JL, Nieh PT, and Walzak MP: Brain metastases from transitional cell carcinoma, J Urol 137: 97 (1987). 6. Kabalin J, Freiha FS, and Torti FM: Brain metastases from transitional cell carcinoma of the bladder, J Urol 140: 820 (1988). 7. Page S, and Asire AJ: Cancer rates and risks, publication No. 85-691, Bethesda, National Institutes of Health, 1985. 8. Davis RP, et al: Isolated central nervous system metastasis from transitional cell carcinoma of the bladder: report of a case and review of the literature, Neurosurgery 18: 622 (1986). 9. Lower WE, and Watkins RM: Case of primary carcinoma of the bladder with metastasis to the brain, Am J Med Sci 167: 434 (1924). lO.McKay HW: Solitary metastasis to the brain from carcinoma of the bladder, Br J Urol 2: 156 (1930). 11. Steinfeld AD, and Zelefsky M: Brain metastases from carcinoma of bladder, Urology 29: 375 (1987). 12. Kies M: Editorial comment: Kabalin JN, et al: Brain metastasis from transitional cell carcinoma of the bladder, J Urol 140: 824 (1988). 13. Mandell S, et cd: Carcinomatous meningitis from transitional cell carcinoma of the bladder, Urology 25: 520 (1985). 14. Fetter TR, et cd: Carcinoma of the bladder: sites of metastases, J Urol 81: 746 (1959). 15. Fadul C, Misulis KE, and Wiley RG: Cerebellar metastases: diagnostic and management considerations, J Clin Oncol5: 1107 (1987). 16. Batson OV: The function of the vertebral veins and their role in the spread of metastases, Ann Surg 112: 138 (1940). 17. Castaldo JE, et al: Intracranial metastases due to prostatic carcinoma, Cancer 52: 1739 (1983).
53
