Fig. 25.1
MRI of 79-year-old man with a history of prostate cancer who presented with diplopia. a Coronal, T1 post-contrast image with arrow demonstrating dural lesion in the right anterior temporal lobe. b Corona, T1 post-contrast image with arrow demonstrating several dural lesions in the right frontal lobe
Leptomeningeal Metastases
Leptomeningeal metastasis from prostate cancer is very rare. It is a late complication of disease, and thereby often associated with hormone refractory disease and a poor prognosis [21]. As patients with prostate cancer survive longer, there may be increased incidence of relapse in the CNS, including in the leptomeninges [22]. Aside from identifying malignant cells on cytology, PSA can also be detected in the CSF [23]. Treatment is palliative with radiation as the backbone of treatment.
Epidural Spinal Cord Compression
The vertebral bodies are a common location for bone metastases in advanced prostate cancer. Prostate cancer accounts for 16% of all malignant epidural spinal cord compression (MESCC) with 5% of patients with prostate developing MESCC [24]. Back pain in this patient population should prompt evaluation for epidural spinal cord compression, as pain often precedes neurologic symptoms by weeks or months and early intervention may prevent deficits. Patients may also present with a myelopathy and bowel/bladder dysfunction, depending on the location of the lesion. Prostate cancer rarely presents as MESCC, which is a marker of advanced metastatic disease [25]. Although the thoracic spine is the most common site of MESCC overall in cancer, the lumbar region is more often affected in prostate cancer [26].
Evaluation and treatment considerations for MESCC from prostate cancer are similar to those from other neoplasms. Importantly, the entire spine should be screened if MESCC is suspected or a lesion is identified, as it may be multifocal. The intent of treatment is palliative and focused on pain control and preservation of neurologic function. Prostate histology and ambulation prior to treatment are favorable predictors of outcome and improvement in neurologic function [27, 28]. Glucocorticoids and opioids are used acutely for pain control. Though high-level evidence is limited, surgical decompression and spinal stabilization should be considered in select patients with spinal instability who are felt to be good surgical candidates [29, 30]. This is particularly true for patients with MESCC from prostate cancer with median survival >9 months [28].
Prostate cancer is highly radiosensitive, and radiation is a cornerstone in the treatment of MESCC. Radiation, usually 30–40 Gy in 10–20 fractions, is an effective method for pain control from MESCC without spinal instability [31]. Surgery is often followed by radiation for improved rates of local control [29, 30]. Radiation is the treatment of choice for the remainder of patients who are not felt to benefit from surgery with high rates of local control and median survival of >9 months [28]. Radiation effectively preserves ambulation in nearly all patients who are ambulatory at presentation. For those who are paretic at presentation, ambulation rates of 52–83% are reported after radiation, though only 20–25% of paraplegic patients will regain their ability to walk [29, 32, 33]. Though courses of hypofractionated radiation and stereotactic radiation can be considered for selected patients with short-life expectancy, protracted courses of 30–40 Gy over 10–20 fractions are recommended with evidence of improved local control rates over shorter courses [34, 35]. Patients with MESCC from prostate cancer who are hormone-naïve may also benefit from androgen deprivation in combination with radiation and/or surgery [29, 32]. Despite effect treatments, however, patients remain at risk of compression at the same site, or a new site, within two years [36].
Paraneoplastic Syndromes
Paraneoplastic syndromes have also been identified in prostate cancer. The anti-Hu antibody is associated with a subacute, distal, sensorimotor polyneuropathy found in patients with squamous cell carcinomas of the prostate [37, 38]. It has also been identified in patients with limbic encephalitis and squamous cell carcinomas of the prostate. Symptoms may respond to treatment of the underlying malignancy or immunotherapy, though overall response rates are low [39]. Anti-Hu antibodies have also been discovered in cerebellar degeneration in patients with prostate cancer [40]. Symptoms include weeks to months of progressive ataxia, dysarthria, diplopia, nystagmus, and ophthalmoplegia. Imaging reveals cerebellar atrophy late in the disease. Lambert-Eaton syndrome, a paraneoplastic disorder affecting the neuromuscular junction whereby an antibody to voltage-gated calcium channel (VGCC) impairs release of acetylcholine from nerve terminus, is rarely seen in patients with prostate carcinoma [41]. Presentation mimics that of myasthenia gravis, only the limbs are predominately weak and oculobulbar muscles are spared. Dermatomyositis has also been described in prostate cancer [42].
Renal Cell Carcinoma
There are 50,000 new cases of renal cell carcinoma diagnosed per year in the USA [43, 44]. The most common histology is clear cell adenocarcinomas, followed by papillary, chromophobe, oncocytic, and collecting duct. RCC is associated with several genetic syndromes including von Hippel-Lindau and tuberous sclerosis. Patients usually present with hematuria, abdominal pain, and palpable flank mass [45].
Localized disease is often surgically curable and, therefore, the recommended treatment in patients who are appropriate surgical candidates. Trials of adjuvant treatment with immunotherapy or anti-angiogenic-targeted therapy (sunitinib and sorafenib) have not improved disease-free or overall survival. Patients with stage I or II disease have five-year overall survival rates of 75–95%. Five-year survival rates of stage III of 59–70% with invasion of vena cava [46, 47] and urine collection system [48] associated with worse prognosis.
Treatment for advanced RCC includes immunotherapy with interleukin-2 (IL-2) and interferon alpha (INF-α). Several tyrosine kinase inhibitors such as pazopanib, sunitinib, sorafenib, and axitinib target the vascular endothelial growth factor (VEGF) pathway. Bevacizumab, the monoclonal antibody against VEGF, has also been shown to improve progression-free survival when combined with INF-α [49, 50]. Everolimus or temsirolimus target the mammalian target of rapamycin (mTOR) pathway. Treatment decisions are based on several prognostic factors, and contemporary median overall survival with stage IV disease is 28–29 months [51–53].
Brain Metastases
The incidence of metastases to the brain in RCC is estimated at 10% (Fig. 25.2a, b) [54]. Brain metastases from RCC also have increased risk of hemorrhage [26] and are more likely to present as a single lesion versus multiple [55]. Median OS is 10 months with poor KPS and increasing number of metastases at diagnoses as poor prognostic factors [56–58]. The approach to treatment is similar to brain metastases from other malignancies with consideration for resection of single metastases majority of patients succumb to systemic versus brain disease [59]. Despite its radioresistance, higher doses of radiation with stereotactic radiosurgery have demonstrated efficacy. For patients with limited number of intracranial metastases, good performance scores, and stable extracranial disease, stereotactic radiosurgery may provide rates of local control 83–95% [60–62].
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Fig. 25.2
MRI of 62-year-old-man with history of renal cell carcinoma who presented with dizziness. a Axial, T1 post-contrast image of homogenously enhancing mass in the right hemisphere. b Axial, FLAIR image demonstrating significant surrounding vasogenic edema
The effectiveness of kinase inhibitors (KIs) —such as VEGFR inhibitors sorafenib and sunitinib and mTOR inhibitor temsirolimus—on control of brain metastases is unclear. Preclinical data suggest synergy and without significant toxicity when combining KIs with radiation [63–65]. In prospective trials of sunitinib in brain metastases from RCC, CNS toxicity was low with one instance of hemorrhage and four seizures [63]. Despite preclinical evidence that KI may be radiosensitizing, outcomes for patients with brain metastases in the KI-era are not markedly changed [56, 57]. Despite small case series suggesting efficacy of KIs as monotherapy for brain metastasis [56, 66], prospective data have failed to demonstrate efficacy [65] and local treatment with surgery and radiation is still favored. Evaluation of brain metastases patients in the expanded-access trials for sorafenib [67] and sunitinib [63] demonstrated response rates of at least stable disease in 74 and 64%, respectively, suggesting efficacy and need for further study [63, 67]. Prospective data have also demonstrated a decrease in incidence of brain metastases in patients treated with sorafenib versus placebo [68].
Leptomeningeal Metastases
Epidural Spinal Cord Compression
RCC commonly metastasizes to bone with spinal involvement in 40% of cases [71]. Spinal metastases risk metastatic epidural spinal cord compression (MESCC), which can have a marked impact on quality and duration of life [72]. Median survival of RCC metastasis to the spine is reported at 8–13 months [73–77].
Evaluation and treatment of MESCC from RCC should be similar to other neoplasms, including evaluation of the entire spine, as disease may be multifocal. The intent of treatment is palliative and focused on pain control and preservation of neurologic function. The radioresistant nature [78] of RCC and poor response to systemic therapy have set a low threshold for surgery. Prognostic factors include Fuhrman grade (a four-grade system based on nuclear size, shape, and nucleoli appearance [79]) of the initial nephrectomy, state of systemic disease, and presurgical neurologic deficits and correlate with outcome after surgery [73]. Patients with spinal instability should also be considered for surgical decompression and stabilization.
Conventional, fractionated radiation is felt to be less effective for patients with radioresistant tumors, such as RCC [28]. However, there is increasing evidence for improved local control rates and symptomatic improvement with radiosurgery in patients with spinal metastases with stable spines [27]. Studies have also demonstrated 80% improvement in neurologic function with epidural spinal cord compression without high-grade compression [80]. Retrospective studies also report local control rates of 80% when radiosurgery doses of 18–36 Gy were used after decompression surgery [81, 82].
Intramedullary Spinal Cord Metastases
Intramedullary spinal cord metastases are rare and account for 4–9% of all CNS metastases [83]. Renal carcinoma is thought to comprise ~4% of all cases of intramedullary metastases and is reported in small case series and case reports [84]. Patients often present first with symptoms of pain, followed by weakness and sphincter dysfunction, that is, often rapid. Patients usually have advanced metastatic disease, including other CNS metastases, though intramedullary metastases may rarely be the presenting symptom [84, 85]. Decisions regarding treatment are dependent on functional status and extent of systemic disease, with surgery reserved for those with controlled systemic disease who are good surgical candidates. Otherwise, radiation treatment is used to palliate and stabilize disease [83, 84].
Paraneoplastic Syndromes
Paraneoplastic syndromes are uncommon in RCC. There are reports of limbic encephalitis in patients with renal cell [86]. Anti-Ri antibodies have been associated with opsoclonus myoclonus syndrome in patients with RCC [87]. Patients present with spontaneous chaotic eye movements of opsoclonus, with myoclonic movements of the trunks and limbs, and cerebellar ataxia. Dermatomyositis has also been seen in RCC [88]. Presenting symptoms include progressive pain and hypertrophy of proximal muscles and violet-colored rash of the face and hands.
Bladder Cancer
Bladder cancer accounts for an estimated 4.5% of malignancies in the USA with an estimated 74,000 cases diagnosed in 2015. It is the fifth leading cause of cancer and much more common in men [1]. The most common histology is transitional cell, followed by squamous cell, adenocarcinoma, small cell carcinoma, sarcoma, rhabdmyosarcoma, and leiomyosarcoma. Spread is through local invasion and hematogenous dissemination and involves liver, lung, and bone [89, 90].
Prognosis and treatment are dependent on histology and staging based on the depth of invasion [91]. Superficial, non-muscle invasive bladder tumors may be amenable to transurethral resection and intravesical delivery of chemotherapy or immunologic agents, such as bacillus Calmette–Guerin (BCG) [91, 92]. Invasive tumors, however, often necessitate neoadjuvant systemic chemotherapy combinations followed by cystectomy. Chemotherapy regimens include MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) [93] or gemcitabine and cisplatin (or carboplatin) [94]. Overall, neurologic complications are infrequent from bladder carcinoma [95].
Brain Metastases
Brain metastases are a rare finding in bladder cancer with reports of 0–7% with longer survivors being more at risk [95, 96]. First, the use of the MVAC regimen, and more recently combination therapy with a platinum and gemcitabine, has significantly improved outcomes in patients with bladder cancer. However, these regimens have limited blood brain barrier penetration, therefore increasing the risk of late CNS relapse [97] with an estimated incidence ~16% [98]. Multiple lesions are more common and are a marker of advanced disease [99]. Median survival is 2–7 months [97, 100, 101]. Treatment consists of surgical resection, when appropriate, and radiation therapy—prospective studies comparing combinations of these treatments are lacking. Retrospective trials have identified the number of metastases, status of extracranial disease, and RPA status as prognostic factors [102, 103].
Leptomeningeal Metastases
Leptomeningeal carcinomatous is noted in case reports for bladder cancer. It is seen in longer survivors of pretreated patients, again indicating the propensity for relapse in the CNS when chemotherapeutics are unable to penetrate the blood–brain barrier (Fig. 25.3a, b) [104, 105]. There are also case reports of transitional cell carcinoma of the bladder presenting as leptomeningeal carcinomatosis [106].
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Fig. 25.3
MRIs of an 80-year-old man with bladder cancer. He had recently received carboplatin and gemcitabine with a complete systemic radiographic response but developed low back pain followed by deafness and gait ataxia. a Coronal T1 post-contrast images reveal patchy bilateral enhancement of VIII nerves. b Sagittal T1 post-contrast image demonstrates enhancement of the distal cord and cauda equina with signal abnormality involving the distal cord and conus
Epidural Spinal Cord Compression
Epidural spinal cord compression from bladder cancer is rare with reports of <2% in the literature and usually presenting with pain [95]. Hematogenous dissemination to bone is the most common mechanism, though erosion from metastasis to the paraspinal lymph nodes and erosion is also reported. Treatment usually includes radiation [95].
Paraneoplastic Syndromes
Several paraneoplastic syndromes have been associated with bladder malignancies [107]. The anti-Ri [108, 109] antibody is associated with opsoclonus myoclonus syndrome in patients with transitional cell carcinoma of the bladder. Patients present with spontaneous chaotic eye movements of opsoclonus, with myoclonic movements of the trunk and limbs, and cerebellar ataxia. Polymyositis [110] and dermatomyositis [111], with progressive pain and hypertrophy of proximal muscles and violet-colored rash of the face and hands, have both been seen in bladder cancer.
Lambert-Eaton syndrome [112] is a paraneoplastic disorder affecting the neuromuscular junction where the antibody to voltage-gated calcium channel (VGCC) impairs release of acetylcholine from nerve terminus. Anti-VGCC antibodies are rarely seen in patients with bladder carcinoma. Presentation mimics that of myasthenia gravis, only the limbs are predominately weak and oculobulbar muscles are spared. Anti-Yo antibodies are associated with cerebellar degeneration in patients with bladder cancer [113]. Symptoms include weeks to months of progressive ataxia, dysarthria, diplopia, nystagmus, and ophthalmoplegia. Imaging reveals cerebellar atrophy late in the disease.
Other
Retroperitoneal metastases may locally invade the lumbosacral plexus causing a plexopathy. Patients commonly present with back pain and may have radiographic evidence of retroperitoneal mass on imaging. Treatment includes radiation [95].
Testicular Cancer
Although testicular cancer is the most common solid malignancy diagnosed in men between 15 and 35 years of age [105], it accounts for <1% of all newly diagnosed cancers in the USA [1]. It is among the most curable solid tumors with five-year survival rates >95% in the USA [1]. Greater than 95% are germ-cell tumors (GCT), which are broadly classified as seminomas or nonseminomatous germ-cell tumors (NSGCTs). Seminomas are more likely to present with localized disease, have a lower tendency to metastasize, and are highly radiosensitive. NSGCTs carry a worse prognosis and are more radioresistant [114]. Metastases occur most often to the chest, retroperitoneum, or neck. Early stage disease may be cured with orchiectomy. However, higher risk patients may require adjuvant chemotherapy; such as bleomycin, etoposide, and cisplatin (BEP) or etoposide plus cisplatin (EP) [115]. Though neurologic complications from testicular cancer are relatively rare, there are several syndromes of particular importance.
Brain Metastases
Brain metastases develop in 0.4–4% of men with metastatic germ-cell tumors and are associated with poor prognosis [116, 117]. Metastases to the brain are more common in nonseminomatous tumors [118]. Patients presenting with synchronous disease at the time of diagnoses are felt to have platinum-sensitive disease and have five-year survival rates of 45% [116]. However, patients who relapse in the brain either during or after chemotherapy treatment have far poorer prognosis with five-year survival rates of 12% [116, 118].
Brain metastases from testicular germ-cell tumors are felt to be sensitive to chemotherapy; first line treatment involves cisplatin and etoposide, both of which have some blood–brain barrier penetration. Surgery or focal radiation may be appropriate in certain clinical scenarios. Whole-brain radiation, however, is reserved for patients with refractory disease given the risk of delayed neurotoxicity [116, 118, 119].
Leptomeningeal Metastases
There are case reports of leptomeningeal carcinomatosis from testicular cancer in patients with seminomatous [120] and nonseminomatous [121–123] tumors. Similar to intracranial metastases, it is likely a marker of advanced disease with CNS relapse of aggressive disease after treatment with therapy that does not cross the blood–brain barrier. Treatment with radiation is usually recommended [122].
Epidural Spinal Cord Compression
Epidural spinal cord compression secondary to metastatic germ-cell tumors is rare and accounts for <1% of spinal metastases [124]. Treatment may include surgical intervention for unstable spine or rapidly deteriorating neurologic function. Radiation may be used for radiosensitive seminomas, or platinum-based therapy given the chemosensitivity of GCT [124, 125].
Paraneoplastic Syndrome
Limbic encephalitis is a constellation of symptoms in behavioral changes, sleep disruption, seizures, and memory impairment. MRI depicts non-enhancing, T2/FLAIR changes most commonly in the temporal lobes. Anti-Ma2-associated encephalitis (also known as anti-Ta) may also affect the diencephalon or brainstem and is found in patients with testicular cancer [126, 127]. Symptoms may also include ophthalmoplegia or other eye abnormalities and sleep disorders [128]. Ma2-associated encephalitis is more responsive to treatment directed against testicular cancer and immunotherapy and is associated with a better outcome than other causes of limbic encephalitis [128, 129]. Dermatomyositis has been associated with testicular cancer [130]. Presenting symptoms include progressive pain and hypertrophy of proximal muscles and violet-colored rash of the face and hands.
Chemotherapy-Related Neurologic Complications
Treatment for testicular cancer is highly dependent on platinum-based therapy. This puts patients at high risk for developing peripheral neuropathy and ototoxicity. The incidence of persistent paresthesias is estimated at 29% for testicular cancers, and neuropathy may persist for years [131]. Ototoxicity is an even more prevalent toxicity from platinum therapy with ~20% long-term survivors reporting tinnitus and hearing loss [131, 132].
Targeted agents used to treat RCC also have associated neurologic toxicities. The VEGFR kinase inhibitors (KIs), such as sorafenib and sunitinib, have been associated with increased risk of hemorrhage and seizures [63]. This has particularly been seen in patients with brain metastases [133]. There are also several case reports in the literature of reversible posterior leukoencephalopathy syndrome (RPLS) in patients with RCC treated with sunitinib [134, 135]. Several of these neurologic toxicities are also seen with bevacizumab, including hemorrhage and RPLS, as well as the risk of intracranial ischemia [136].
Patients with prostate cancer treated with androgen deprivation therapy will frequently experience fatigue, insomnia, and cognitive changes. Though it is unclear if this is a direct medication or result of androgen withdraw, there is no clear correlation with testosterone levels [137]. Prostate cancer patients treated with taxanes, such as docetaxel or cabazitaxel, are at risk for developing a sensory neuropathy. Though less neurotoxic than paclitaxel, sensory and motor neuropathies are seen more often in cumulative doses in excess of 400 mg/m2 for docetaxel [138]. Cabazitaxel appears less neurotoxic with peripheral neuropathy noted in <20% of patients [139, 140].
Conclusion
In conclusion, tumors of the genitourinary system are a common and heterogeneous group of malignancies affecting people of all ages with varying prognosis. Neurologic complications from these malignancies are an important cause of morbidity and mortality and can result from metastatic disease and treatment. As outcomes from patients with these malignancies improve, neurologic sequelae from delayed relapse and chronic treatment-related effects are likely to increase. Management of these neurologic complications from genitourinary cancer is an important focus for future research.
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Hoffman RM, Koyama T, Fan KH, Albertsen PC, Barry MJ, Goodman M, et al. Mortality after radical prostatectomy or external beam radiotherapy for localized prostate cancer. J Natl Cancer Inst. 2013;105(10):711–8.PubMedPubMedCentral
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