Clinical manifestations

Presentation and course

The clinical manifestations of cerebrovascular disease in cancer patients may differ from that of patients without cancer. In both cases, the neurologic deficits present acutely. Rather than presenting with focal cerebral signs, however, stroke in cancer patients can be multifocal at time of onset and manifest with encephalopathy. The underlying cancer type can play a role in determining the time from cancer diagnosis to stroke. Patients with hematologic malignancies, for example, experience shorter average times from diagnosis to stroke manifestation than those with solid tumors (110).

Typically, cerebral infarction from nonbacterial thrombotic endocarditis presents with focal neurologic deficits; yet, because of the multiplicity of infarctions there may also be a superimposed encephalopathy (111). Interestingly, the incidence of cerebral ischemia is noticeably higher with nonbacterial thrombotic endocarditis than with infective endocarditis (31). In contrast, cerebral intravascular coagulation, unaccompanied by nonbacterial thrombotic endocarditis, commonly results in encephalopathy; however, there may be transient superimposed focal neurologic deficits (27). The clinical course of cerebral infarction caused by these coagulation disorders is progressive, and the manifestations often fluctuate. Leptomeningeal metastases should be considered in cancer patients with evidence of stroke affecting multiple vascular territories, including the spine. Patients can manifest neck or back pain along with spinal tenderness, cranial neuropathies, and signs and symptoms suggestive of myelopathy; less frequently, they present with meningitis or focal cerebral infarction (31).

Cerebral venous sinus thrombosis generally presents with headaches or seizures (15; 31). The most frequently involved venous sinus is the superior sagittal sinus (110). There may be accompanying focal or diffuse cerebral neurologic deficits if cerebral edema, venous infarction, or hemorrhage occur. In contrast, venous occlusion produced by skull or dural metastasis presents subacutely with signs of increased intracranial pressure (eg, headache, vomiting, papilledema) that may be associated with focal or diffuse cerebral signs (110). Spontaneous recovery can occur when venous occlusion is caused by coagulopathy. However, the clinical course can be progressive if left untreated. Venous occlusion associated with L-asparaginase usually occurs during or after induction therapy to treat leukemia and can resolve spontaneously.

Fungal septic cerebral infarction can be seen in cancer patients treated with immunosuppressant agents. Patients are usually febrile and present with acute focal deficits, seizures, or encephalopathy. Focal signs and seizures are more common in aspergillosis, whereas encephalopathy is more common in candidiasis. Patients with septic fungal embolism can have a progressive course. Isolation of the microorganism can be difficult; therefore, a high index of suspicion is critical to making the diagnosis (31).

Cerebral tumor embolic infarcts present acutely (100). Neurologic deficits may progress in patients with systemic carcinoma because of cerebral tumor growth. In contrast, growth of tumor embolic material is rare in patients with atrial myxoma and papillary fibroelastoma. Cerebral granulomatous angiitis complicating Hodgkin disease or leukemia may produce headache, fever, confusion, seizures, obtundation, or hemiparesis. Approximately 40% of patients with granulomatous angiitis may have transient ischemic attacks, and 25% may have seizures. Self-limited symptoms suggesting transient ischemic attacks can occur during therapy with interleukin-2. Posterior reversible encephalopathy syndrome (PRES) is a recognized complication of systemic or intrathecal chemotherapy or antiangiogenic targeted therapies including bevacizumab, as well as cytotoxic chemotherapies, such as taxanes, platinum derivatives, and vinca alkaloids (120). In addition, this syndrome has been observed in patients with lymphoproliferative disorders treated with stem cell transplantation and immunosuppressive treatments such as tacrolimus, cyclosporine, everolimus, and sirolimus (109). Clinically, PRES manifests with vomiting, confusion, seizures, cortical blindness, and motor deficits.

Intravascular lymphomatosis (IVL) is a rare form of extranodal B-cell non-Hodgkin lymphoma that occurs within the lumen of small and medium vessels. Intravascular lymphomatosis typically presents subacutely with multiple cerebral infarcts or encephalopathy. Hematologic malignancies may also be implicated in CNS leukostasis and hyperviscosity syndromes that can result in hemorrhagic and ischemic stroke. For example, acute leukemia can cause hyperleukocytosis (defined as white blood cell count greater than 100,000 per mm3), leading to blast cell accumulation in the lumen of medium-sized vessels of different organs, including the CNS and lungs. The symptoms may fluctuate or even reverse due to changes in leukocyte count. Multiple myeloma, in comparison, can produce significantly elevated protein levels, resulting in hyperviscosity syndrome (31).

In some instances, stroke is the first manifestation of cancer; however, cryptogenic stroke alone does not always warrant workup for occult malignancy. Cancer should be considered as an etiology for acute ischemic stroke in patients with risk factors for malignancy, such as old age and history of smoking, and elevated levels of coagulation or inflammatory markers, such as D-dimer and C-reactive protein (115).

Acute or chronic disseminated intravascular coagulation can result in hemorrhage, thrombosis, or a combination that involves either the systemic or cerebral circulation. In addition, cerebral hemorrhage and thrombosis can occur in cancer patients due to altered hemostatic function induced by antineoplastic therapies. Examples of anticancer agents that have been known to increase the risk of thrombosis are platinum and taxane chemotherapy agents, targeted therapies such as angiogenesis inhibitors and tyrosine-kinase inhibitors, and immunomodulatory agents (87).

Ischemic symptoms associated with the administration of chemotherapy do not recur when the medication is discontinued. In comparison, symptoms of carotid atherosclerosis associated with neck radiation can be recurrent and progressive.

In relation to intracranial hemorrhage, subdural hemorrhage usually presents with confusion and lethargy (focal cerebral signs are less common) (50). Subarachnoid hemorrhage manifests with hyperacute severe headache and may be accompanied by sudden deterioration of consciousness. A unique challenge in cancer patients is recognizing signs of hemorrhage in patients with primary or metastatic brain tumors. Brain hemorrhage can often be the presenting sign of cerebral metastasis (56). These patients can experience chronic cerebral symptoms as a result of their brain metastasis, and superimposed acute changes should raise concern for hemorrhage into their brain tumor or tumor borders. Interestingly, in metastatic brain tumors, hemorrhage is typically located around the tumor borders, whereas in primary gliomas, bleeding appears within the tumor itself (31). The neurologic deficits can progress further if the brain hemorrhage produces significant mass effect or if the underlying coagulopathy is not corrected.

Cerebral hemorrhage or thrombosis may also be a result of the tumor on cerebral vessels. Cerebral hemorrhage can also be secondary to a systemic hemostatic disorder. In this case, patients may experience concomitant systemic bleeding, which may involve mucosal surfaces, retinae, gastrointestinal and genitourinary tracts, skin, or venipuncture and bone marrow aspiration sites. Paradoxically, given the increased thrombogenicity, there may also be venous thrombosis, limb thrombophlebitis, pulmonary embolism, myocardial infarction, or limb arterial embolism. A syndrome similar to the hemolytic-uremic syndrome is associated with the administration of adjuvant chemotherapy for carcinoma (especially gastric adenocarcinoma) and may produce seizures, loss of consciousness, or confusion. It also typically produces dyspnea, hypertension, and peripheral edema (47).

Prognosis and complications

Zhang and colleagues reported a retrospective comparison of the survival of patients hospitalized with cerebral infarction who did or did not have an associated cancer, and the overall survival was worse among cancer patients (136). A D-dimer level greater than 5.50 mg/dL, systemic metastases, and diabetes are independent predictors of poor survival in patients with cancer and cryptogenic stroke (118). A confounding variable is that the duration of survival is often dictated by the underlying tumor or systemic thromboembolic or hemorrhagic complications. Retrospective studies indicate that the survival rate for patients with hemorrhage into metastatic brain tumor does not differ from those patients with non-tumoral hemorrhage, except for those with large hemorrhages that are life-threatening (50). Independent factors associated with poor 30-day survival after intracranial hemorrhage in cancer patients include impaired consciousness, multiple foci of hemorrhage, hydrocephalus, no ventriculostomy, treatment of increased intracranial pressure, and absence of a primary brain tumor (92).

Limited data are available regarding the survival rate for patients with ruptured neoplastic aneurysms. The prognosis for recovery and survival after brain hemorrhage associated with hyperleukocytosis early in leukemia or acute disseminated intravascular coagulation associated with acute promyelocytic leukemia has improved in recent years because of aggressive methods to treat the underlying tumor.

Survival in nonbacterial thrombotic endocarditis may be short because many patients have advanced cancer; yet, death may also be a result of myocardial infarction or pulmonary embolus because of the associated coagulopathy (111). Patients with nonmetastatic superior sagittal sinus occlusion can recover completely, especially if it occurs early in the course of cancer when the tumor is responding to treatment. The prognosis is poor, however, when the deep cerebral venous sinuses are involved (113). When non-metastatic superior sagittal sinus occlusion occurs late, the prognosis is poor, especially if the tumor is not responding to treatment (119). With metastases as the underlying etiology, the outcome may worsen, unless therapy is directed to the adjacent skull or dural tumor (77). Fungal septic infarction carries an elevated mortality despite administration of antifungal therapy. Infarctions from tumor emboli and leptomeningeal metastasis are rare, and the prognosis is directly related to the presence of metastatic disease. Subsequent embolization can be prevented in patients with cardiac myxoma by removing the tumor. However, aneurysm may develop as a delayed consequence of embolization. Successful surgical treatment of radiation-induced carotid stenosis may reduce ischemic symptoms, but data are limited regarding the survival rate and cause of death in such patients. In patients with radiation-induced stenosis, there appears to be a higher rate of in-stent restenosis (134). Carotid artery rupture is associated with high mortality. Intravascular lymphomatosis can be stabilized with steroids, radiation, or chemotherapy (17). However, the prognosis is poor, often because the diagnosis is made late in the disease. The probability for recovery from cerebral thrombosis caused by L-asparaginase is good. Survival in other cerebral infarctions related to chemotherapy covers a wide spectrum; the neurologic symptoms may be mild and transient, or fatal.

Clinical vignette

The patient was a right-handed, 63-year-old woman diagnosed with metastatic pancreatic cancer two months. Her prior medical history was otherwise unremarkable, and there were no known stroke risk factors. She received one cycle of investigational chemotherapy, and two days after the second dose of chemotherapy, she awoke with inability to speak. On examination a few hours later, she had marked reduction in speech output associated with paraphasic errors. She was unable to repeat. The remainder of the neurologic examination was normal. Her vital signs were normal; there was no cardiac murmur and no neck or ocular bruits. Table 1 shows the hematologic and coagulation studies performed that day (Day 1). There was a decrease in the platelet count compared to two weeks prior (Day -14) and the D-dimer was elevated. CT scan was unremarkable. However, MRI scan administered the next day showed abnormal tissue density in a gyriform pattern in the left tempoparietal area, consistent with infarction as well as ischemic changes in the periventricular regions of both cerebral hemispheres and in the left pons. Cranial MRA showed a loss of signal in the distal left middle cerebral artery. The extracranial MRA was normal aside from minimal atherosclerosis in the left internal carotid artery. Transthoracic echocardiography was normal aside from aortic sclerosis. Her neurologic symptoms improved considerably over the next 48 hours, but she was left with slight hesitancy in speech and occasional paraphasic errors.

Table 1. Hematologic and Coagulation Parameters

She was difficult to rouse one morning approximately two weeks later (Day 16), and she was brought to the emergency room. She presented to the emergency department obtunded. Her eyes were deviated to the right. She spontaneously moved all limbs. The deep tendon reflexes were symmetric, and the plantar reflex was flexor bilaterally. The brain MRI and MRA showed no change from the previous MRI and MRA. There was a further decrease in platelets and a further elevation of the D-dimer. In addition, fibrin monomers and fibrin split products were abnormal. EKG showed a possible septal infarct of indeterminate age. EEG showed diffuse slowing with triphasic waves. CT scan of the abdomen showed progression of hepatic metastases and decreased attenuation in the spleen consistent with an infarct. A clinical diagnosis of chronic disseminated intravascular coagulation was made, most likely in association with nonbacterial thrombotic endocarditis. As a result of the progression of her primary tumor, now considered incurable, anticoagulation was not administered.

The patient’s level of consciousness waxed and waned over the first few days; at times she was alert and followed commands, and at other times was deeply obtunded. She became progressively more obtunded and could not be aroused. The right arm became spastic, and there was intermittent jerking of the right arm. She developed Cheyne-Stokes respirations. The left eye was slightly elevated above the right eye. Three days after the onset of the symptoms, she had a small amount of hematuria. Five days after admission, the left calf became swollen and warm. Table 1 shows further decrease in platelets and fibrinogen and increase in the prothrombin and activated partial thromboplastin times (Day 21). Her temperature rose to 101°F. She died two weeks after admission.

General autopsy revealed adenocarcinoma of the pancreas with diffuse abdominal metastasis and microscopic metastasis to the lungs and right adrenal gland. There was severe bilateral bronchopneumonia. Sterile platelet-fibrin vegetations consistent with nonbacterial thrombotic endocarditis were observed on the mitral valve and multiple recent infarctions involving the spleen, both kidneys, and myocardium. Neuropathological examination revealed a large recent left frontal lobe infarction in the distribution of the proximal anterior and middle cerebral arteries, with organizing occlusive thromboemboli within the proximal left anterior and middle cerebral arteries and organizing thromboemboli with partial recanalization of the distal middle cerebral artery. Thrombi were present in the subarachnoid arteries overlying the left inferior frontal lobe. In addition, there were recent infarcts involving the right parietal lobe, right superior cerebellar cortex, left basis pontis, and left basal ganglia. Old infarcts were present involving the left superior temporal and inferior parietal gyri, left paracentral cortex, and left thalamus associated with microscopic thromboemboli.

This case illustrates characteristic neurologic manifestations of nonbacterial thrombotic endocarditis, which in this instance were the presenting signs of this coagulopathy, prior to systemic manifestations. Nonbacterial thrombotic endocarditis typically presents with focal neurologic signs, most commonly aphasia. Most patients also develop encephalopathy that characteristically waxes and wanes but ultimately is progressive. Systemic findings and laboratory results that were consistent with a chronic coagulopathy include myocardial infarction, calf phlebitis, a progressive decrease in platelets and fibrinogen, elevated D-dimer and prothrombin, and activated partial thromboplastin times. Autopsy showed widespread systemic thromboemboli. The investigational drug that this patient received is not known to cause significant thrombocytopenia; thus, the progressive decrease in platelets was most likely related to the consumption of platelets from the coagulopathy. Occasionally, the drug is associated with systemic thromboembolic complications, such as clotting of indwelling venous catheters and deep vein thrombosis. It is possible that the drug contributed to the coagulopathy that resulted in nonbacterial thrombotic endocarditis, but a more likely cause is the underlying tumor; pancreatic cancer is commonly associated with clinically significant thromboembolic complications, even without therapy, and sometimes as the presenting sign of the cancer. The neuropathological examination showed infarctions of various ages in multiple vascular territories due to the coagulopathy. The likelihood is high that the left middle cerebral artery occlusions were due to embolization from the heart, and the remainder was due to in situ thrombosis from coagulopathy.

Biological basis

Etiology and pathogenesis

Intracranial hemorrhage. The most common cause of symptomatic intracerebral hemorrhage in cancer patients is altered coagulation function that is directly related to the tumor or its therapy. The direct spread of tumors to the brain, cerebral infection, and vascular toxicity of antineoplastic therapy are other important causes.

In acute disseminated intravascular coagulation, hemorrhage may coexist with thrombosis. The mechanisms involved in this paradoxical association are complex and not fully understood. Procoagulopathy, inflammation, and cell proliferation are involved in thrombogenicity. In addition, tumor cells secrete microparticles with elevated D-dimer levels in the bloodstream. These and other observations have led many to believe that cancer-associated thrombosis is, in part, directly related to the proliferation and spread of cancer cells (125). From the mechanistic standpoint, tumor cells release different mediators, such as tissue factor, factor X, and other procoagulant proteins, which activate the coagulation cascade and result in thrombus formation (08). Tumor cells also stimulate neutrophils and secrete mucins that upregulate the expression of adhesion molecules leading to inflammation. Brain tumors, in particular, can also express transmembrane glycoproteins, such as podoplanin and tissue factor, which activate platelet aggregation (91; 14). These factors as well as the presence of circulating tissue factor and D-dimers correlates with venous thromboembolism in gliomas (14).

Activation of fibrinolytic pathways and tumor-induced neovascularization with abnormal endothelial lining are implicated in the concomitant hemorrhage that can occur with thrombosis. Acute promyelocytic leukemia is often complicated by acute disseminated intravascular coagulation caused by the release of procoagulant material from progranulocytes. This can result in cerebral and systemic hemorrhages. In patients with leukemia who experience brain hemorrhage at relapse or at failure to induce remission, disseminated intravascular coagulation may be present; yet, thrombocytopenia, liver failure, and sepsis also contribute to the coagulopathy (50). Hemorrhages caused by coagulopathy are usually located in the cerebral white matter and are more often single compared to hemorrhages caused by leukemic infiltration of the brain.

Hemorrhage into metastatic brain tumors may result from rapid tumor necrosis or from the rupture of neoplastic or adjacent cerebral blood vessels from rapid tumor growth (76). Melanoma, germ cell tumors (especially choriocarcinoma), and papillary thyroid, hepatocellular, and lung cancers are the most common brain metastases reported as associated with hemorrhage. In some tumors, particularly choriocarcinoma, the underlying metastasis may be microscopic. Intracranial hemorrhages that result from a ruptured neoplastic aneurysm are caused by the destruction of the arterial wall from a tumor embolus and subsequently restored blood flow. Brain hemorrhages may be multiple and usually rupture into the brain parenchyma. Parenchymal brain hemorrhages occurring in the setting of extreme elevation of the peripheral blast count in leukemia (hyperleukocytosis) are associated with cerebral leukostasis (plugging of thin-walled vessels) and parenchymal leukemic nodules. Hyperleukocytosis is most common in acute myelogenous leukemia (132). The mechanism of hemorrhage is disputed but is likely a combination of hyperviscosity, blood vessel damage from the leukostasis, and rupture of blood vessels by the leukemic nodules. Hemorrhages associated with hyperleukocytosis are localized in the white matter, but may extend into the ventricles or subarachnoid space. Leukostasis caused by hyperleukocytosis also commonly affects the lungs to varying degrees and leads to acute respiratory failure (31).

In leukemia, acute subdural hematoma is most commonly due to thrombocytopenia or disseminated intravascular coagulation. Graus and colleagues reported a preponderance of subdural, rather than parenchymal, hematomas in leukemic patients undergoing allogeneic or autologous bone marrow transplants (51). Typically, the patients had acute myelogenous leukemia and severe refractory thrombocytopenia. In contrast, chronic subdural hemorrhage in leukemic patients is more often associated with dural leukemic infiltration (106). A possible association exists with subdural hematoma, hyperleukocytosis, and prior lumbar puncture in acute leukemia (59). Carcinoma (typically prostate and gastrointestinal malignancies) or lymphoma with metastasis to the dura may also produce subdural hemorrhage from spontaneous hemorrhage of the tumor, from rupture of the inner dural vessels because the vessels in the external layer are obstructed by tumor, or from erosion of meningeal vessels by the tumor (112). Sometimes the tumor is microscopic at postmortem examination. Skull metastasis rarely underlies epidural hematoma (54). Subarachnoid hemorrhages are usually caused by thrombocytopenia and are rarely associated with leptomeningeal metastasis.

Cerebral hemorrhage can be a complication of chemotherapy if severe thrombocytopenia results. L-asparaginase, often used in the induction therapy of leukemia, can produce brain hemorrhage. L-asparaginase increases fibrinolysis and depletes plasma proteins involved in coagulation. However, the precise mechanism of altered coagulation function induced by this drug is unknown. A hemolytic-uremic-like syndrome that results from chemotherapy (particularly mitomycin) administered for carcinoma can produce brain hemorrhage. This syndrome can also occur in patients with carcinoma who have not received mitomycin, and the mechanism is unknown (47). Bevacizumab, a humanized monoclonal antibody that targets the vascular endothelial growth factor receptor, is typically used in the treatment of a variety of systemic and brain tumors. This drug carries a small risk of systemic or cerebral thrombosis or hemorrhage. Concomitant anticoagulation may increase the risk of cerebral hemorrhage (95); however, this has not held true in all studies (98). In a series of children with systemic cancer and brain tumors, intracranial hemorrhage during cancer treatment was associated with treatment for hydrocephalus, coagulopathy, thrombocytopenia, and hemorrhage into the tumor. In patients who developed a brain hemorrhage after cancer treatment, brain radiation was a possible contributor (68). Radiation-induced cerebral aneurysms are a rare complication of therapeutic radiation for skull base or nasopharyngeal cancers. In addition, some species of fungal infection can disrupt the vascular elastic lamina, leading to cerebral aneurysmal formation and hemorrhage.

Ischemic stroke. The pathogenesis of cancer-associated ischemic stroke is complex and can involve hypercoagulability, direct tumor effects, and treatment-associated factors.

The majority of patients with advanced solid tumors have laboratory evidence of clotting activation at diagnosis. The mechanism for this phenomenon remains poorly understood. However, the results obtained in observational studies suggest that cancer patients with stroke have elevated levels of markers of procoagulability (D-dimer and thrombin-antithrombin) and endothelial integrity (thrombomodulin), as well as increased burden of cerebral microemboli (94). This observation suggests that hypercoagulability and embolism play an important role in the pathogenesis of cerebral ischemia. The mechanism for this remains poorly understood, and its relationship to subsequent thromboembolic episodes is uncertain. Cerebral infarction in patients with nonbacterial thrombotic endocarditis is due to a combination of embolization of valvular platelet-fibrin vegetations to the brain and cerebral intravascular coagulation, both of which are related to an underlying coagulopathy (111). Medium and small vessels may be affected. The resulting infarctions are single or multiple and may be hemorrhagic. Nonbacterial thrombotic endocarditis is most commonly associated with adenocarcinoma, especially mucin-producing carcinoma of the lung or gastrointestinal tract, and lymphoma (37).

Mucinous adenocarcinomas can also be complicated by intravascular mucinosis and thrombosis with brain infarction. The hallmark of cerebral intravascular coagulation is fibrin occlusion of multiple small arteries, veins, or capillaries resulting in multiple infarctions or petechiae. Usually, these occur in the white matter more than in the gray matter (27; 99). Cerebral intravascular coagulation is reported most commonly with leukemia, lymphoma, and breast cancer.

Tumors can also have a direct effect on cerebral vessels. In intravascular lymphomatosis, multiple cerebral vessels become occluded by intraluminal proliferating lymphoma cells. The mechanism of infarction in leptomeningeal metastasis is tumor cell invasion of the Virchow-Robin spaces, which produces occlusion or spasm of the penetrating arteries. In addition, intracranial and extracranial tumors can cause direct compression of major cerebral vessels, which compromises cerebral blood flow (32). Falcine meningiomas often will infiltrate the superior sagittal sinus impeding venous outflow. Cerebral tumor emboli usually gain access to the systemic arterial circulation via the pulmonary circulation; therefore, cerebral tumor emboli are most common in patients with primary or metastatic lung cancer. In some patients with lung cancer, the embolization occurs during manipulation of the lung at thoracotomy. Embolization can occur even with small peripheral lung tumors (12).

With regard to treatment-associated factors, different cardiovascular complications have been described in association with anticancer treatments (09). For example, immune checkpoint inhibitors have been linked to endocarditis and myocarditis as well as stress cardiomyopathy (105). VEGF inhibitors and proteasome inhibitors have been associated with hypertension and atrial fibrillation. In addition, heart failure has been described in patients receiving treatment with anthracyclines, alkylating agents, and tyrosine kinase inhibitors (45). Intravenous bisphosphonate is often used in patients with bone metastases and appears to impart an increased risk of atrial fibrillation and stroke (130). The third-generation breakpoint cluster-Abelson tyrosine kinase inhibitors ponatinib and nilotinib, used to treat chronic myelogenous leukemia, were found to have an increased incidence of stroke compared to imatinib. It was proposed that these medications may exacerbate traditional risk factors and increase smooth muscle proliferation (46). Immunosuppression is common in cancer patients and plays an important role in cancer-associated stroke.

Septic cerebral infarction results from embolization of septic material to the brain and is typically caused by fungal organisms complicating immunosuppression in patients with leukemia or those who have undergone bone marrow transplantation (29; 62). Candida and aspergillus species are the most common. The infarctions are usually multiple and may be hemorrhagic. If left untreated, then they will evolve into abscesses. Aspergillus, in addition, can have an angioinvasive presentation characterized by progressive stenosis of the large cerebral vessels (75).

The precise role of systemic chemotherapy and hormonal therapy for cancer treatment in cerebral ischemia is uncertain. Treatment-related cerebral infarctions result from direct damage to intracranial or extracranial cerebral vessels or by other speculative mechanisms, including platelet activation, perturbation of hemostasis, vasculitis, and vasospasm.

Women with breast cancer have an increased risk of cerebral infarction compared to the general population (97). It is unclear if the infarctions are due to tamoxifen therapy. In a meta-analysis of breast cancer patients, it was found that tamoxifen administration was associated with a small risk of ischemic stroke (16). However, in a case-control study, no association with tamoxifen was found (42). Cisplatin, particularly when used in combination chemotherapy, carries a small risk of systemic and cerebral thrombosis (74; 38). In rare instances it causes PRES. In a retrospective study of 1559 patients with advanced lung or prostate cancer, 28 cerebral ischemic events (transient ischemic attack or cerebral infarction) were identified. No association between these events and the administration of a matrix metalloprotease inhibitor, with or without platinum-based chemotherapy, was found. The events were, however, predicted by the presence of distant metastases in the liver or lungs (07). In some patients, a hemolytic, uremic-like syndrome develops after combination of chemotherapy with cisplatin or the sole use of mitomycin.

Radiation-induced extracranial vasculopathy produces ischemia by atherosclerotic embolization to the brain or by hemodynamically significant arterial stenosis (05). Dorresteijn and colleagues (36) reported an increase in intima-media thickness of irradiated carotid arteries detected on ultrasound in patients treated for parotid tumors as compared with non-irradiated arteries. The changes were more significant with longer post-radiation intervals. Histologically, it is indistinguishable from typical atherosclerosis, but the distribution is usually more extensive and involves the common carotid artery, localized to the field of radiation. Neck radiation administered for head and neck cancers and lymphoma produces or accelerates carotid artery atherosclerosis (35). A report identified that long-term survivors of childhood Hodgkin disease who received mantle radiation are at increased risk for stroke, presumably related to carotid artery vascular injury or cardiac valvular disease (11). Stereotactic radiosurgery is rarely complicated by cerebral infarction. Moyamoya syndrome can result from cranial irradiation in childhood (65; 80). Emergency carotid artery ligation to treat carotid artery rupture complicating head and neck cancer therapy can result in extensive cerebral hemisphere infarction and death. The biological basis for the association of cerebral granulomatous angiitis with Hodgkin disease or leukemia is unknown. Some experts consider it an antibody negative paraneoplastic syndrome (82).

Central venous thrombosis and PRES. Spontaneous occlusion of the superior sagittal sinus occurs in patients with solid tumors, lymphoma, or leukemia. In a retrospective review of stroke in children treated for acute lymphoblastic leukemia, a prevalence of 0.47% was found, all due to venous thrombosis (113). It is likely to be related to a coagulation disorder associated with the tumor or chemotherapy. Many of these occlusions recanalize and are not detected at autopsy. Skull or dural tumors, typically meningioma may compress or infiltrate the superior sagittal sinus and lead to stasis and thrombosis. This type of venous occlusion is found more often at autopsy. Venous infarction from superior sagittal sinus occlusion is often hemorrhagic.

PRES can occur in patients with cancer, particularly in those with hematologic malignancies, post-allogeneic hematopoietic cell transplantation, and severe hypertension. In addition, PRES has been described in association with different cancer treatments, including tacrolimus (and, rarely, sirolimus), everolimus, cyclosporine, etoposide, anlotinib, capecitabine, bevacizumab, pazopanib, sunitinib, cetuximab, sorafenib, and trastuzumab (44; 49; 102; 34; 103; 104; 22; 60; 01; 89; 86; 90; 122). PRES is caused by endothelial injury or dysregulation, which leads to increased vascular permeability and vasogenic edema. Mechanistically, increased levels of vasoconstrictive, angiogenic, and proinflammatory mediators have been associated with this condition. However, its exact pathogenesis has yet to be fully elucidated (40).

Epidemiology

Few population-based studies of cerebrovascular disorders in cancer patients have been performed. However, in a study of 100 critically ill patients with cancer, 20 were found to have cerebrovascular disease (71). A prospective population-based study using 327,389 pairs of cancer patients and matched controls from the Surveillance, Epidemiology, and End-Results Medicare linked database demonstrated an association between incident cancer and stroke in the following three months, with cumulative incidence rates of stroke of 5.1% in patients with lung cancer (1.2% in controls), 3.4% in pancreatic cancer (1.3% in controls), 3.3% in colorectal cancer (1.3% in controls), and 1.5% in breast cancer (1.1% in controls) (93). The excess risk attenuated over time and was no longer present beyond one year. In both treated and untreated cancer patients a critical lack of prospective studies has been executed correlating neurologic evaluation with coagulation function and evidence of systemic thromboembolic or hemorrhagic complications. Most clinical reports are retrospective or anecdotal. One retrospective clinical review (21) determined the cause of cerebral ischemic events in 33 patients with cancer. The most common cause identified was atherosclerosis, followed by a hypercoagulable state. However, less than one third of patients had complete laboratory investigations for disseminated intravascular coagulation, and many others did not undergo complete evaluations for the cause of infarction. A retrospective study of cerebral infarction in cancer patients found embolic strokes to be slightly more common than non-embolic ones. Atherosclerosis was an uncommon cause of infarction. Lung cancer was the most common underlying cancer (18). Lung cancer patients that have received surgery plus irradiation appear to have a 2-fold increase of ischemic stroke over patients treated with surgery alone (58). A population-based study of patients with cervical cancer in Taiwan found an increased risk of ischemic stroke particularly in younger patients (123). In a large population-based study, the additional risk of ischemic stroke associated with ovarian cancer was particularly prominent in women under the age of 50 (67). Small vessel ischemic changes in the brain may actually be protective against the development of brain metastases in lung cancer patients (83). A precise diagnosis of the cause of infarction or hemorrhage is often established only at autopsy. The most comprehensive study of cerebrovascular disease in cancer patients is an autopsy study conducted by Graus and colleagues that documented the frequency and type of CNS vascular disorders in 3426 patients dying with cancer who underwent neuropathologic examination (50). Five hundred patients (14.6%) had pathologic evidence of cerebrovascular disease, and almost half of them were symptomatic. This study may overestimate the frequency of cerebrovascular disease because a likelihood exists that patients who experienced cerebral symptoms underwent neuropathologic examination more often than those who did not. Yet, this study provides the most reliable data currently available associating the types of cerebrovascular disease with cancer and its treatment.

Prevention

The risk for stroke in cancer patients varies depending on the type of cancer, the extent of systemic and CNS metastasis, and the type of antineoplastic treatment. In cancer patients, the risk factors considered significant for symptomatic cerebrovascular disease in patients without cancer (eg, hypertension, diabetes, coronary artery disease, and age) are not as significant as the pathophysiologic effects of cancer and its treatment.

Hyperleukocytosis, usually occurring at the presentation of acute leukemia, is a risk factor for intracerebral hemorrhage. Emergency administration of antimetabolites and leukapheresis are the standard treatments to reduce the risk of brain hemorrhage by lowering the peripheral blast count. A retrospective study documents that leukapheresis effectively reduces early mortality due to systemic or CNS hemorrhage, though not long-term survival (13). Increased cerebral blood flow has been reported following leukapheresis in acute myelogenous leukemia (61). This study is contradicted by a larger retrospective review by Chang and colleagues, which focused on the rate of CNS hemorrhage in acute myeloid leukemia patients with hyperleukocytosis who were pretreated or not with cranial irradiation and leukapheresis (20). No difference in early mortality was identified. The reason for these disparate findings is not clear.

Acute disseminated intravascular coagulation, accompanying acute promyelocytic leukemia, is also a risk factor for intracerebral hemorrhage. Prophylactic heparin, chemotherapy, and all-trans retinoic acid are effective in reducing the risk of brain hemorrhage in this setting (72). However, cerebral venous thrombosis has been reported with the use of all-trans-retinoic acid (26). Although no prospective studies to document this have taken place, it would seem rational that prompt therapy of coagulation disorders, with attention to replacing clotting factors or administration of anticoagulation, along with therapy of the tumor and sepsis would reduce the cerebral hemorrhagic complications of other cancer patients with acute or chronic intravascular coagulation. Prophylactic heparin or low-dose oral anticoagulants are effective in reducing some systemic thromboembolic complications of cancer (ie, deep vein thrombosis and indwelling catheter thrombosis), but they have not been studied in the subgroup of patients with cerebrovascular disease. The administration of anticoagulants and head trauma may be risk factors for subdural hemorrhage in some patients with solid tumors (85).

The use of steroids and other immunosuppressants are risk factors for fungal infection in patients with leukemia or those undergoing bone marrow transplant. Radiation, infection, and unintentional percutaneous fistulas are risk factors for carotid artery rupture after head and neck tumor resection. Some authors suggest routine carotid duplex ultrasound screening in patients who have received neck radiation in order to detect carotid stenosis (69). The administration of low-dose heparin may reduce the risk of cerebral infarction in patients undergoing carotid ligation to treat a ruptured carotid artery. In many other conditions, cerebrovascular complications related to cancer are not preventable because the underlying disease or coagulation disorder is difficult to control. However, prompt recognition of the disorder will help to distinguish it from other neurologic complications of cancer and can lead to therapy to ameliorate symptoms or prevent additional cerebrovascular events.

Finally, the risk of cerebrovascular injury in cancer patients, particularly those with markedly elevated risk, can likely be mitigated by many of the same management elements used for primary and secondary stroke prevention in the general population. These include diet, exercise, and blood pressure/glucose/cholesterol control.

Differential diagnosis

In patients with solid tumors, sudden focal neurologic signs from cerebrovascular disease may be confused with the acute presentation of cerebral metastasis. Cerebral metastasis may present acutely because of a seizure or rapid expansion of the tumor. In many cancer patients, cerebral hemorrhages or infarctions are multiple and, thus, present in an atypical fashion compared with the unifocal hemorrhage or infarction found in patients without cancer. In addition, cancer patients with cerebrovascular disease often show progressive neurologic deterioration rather than early recovery. In this setting, the most important differential is encephalopathy, which in cancer patients is usually due to metabolic abnormalities, hypoxia, or sepsis. In addition, the differentiation between intracerebral hemorrhage from hemorrhagic metastasis may be challenging and require serial brain imaging.

Diagnostic workup

Brain MRI and CT scans are most helpful in identifying cerebral hemorrhage or infarction. Clues to hemorrhages from coagulation disorders or brain metastasis are multiple hemorrhages in an atypical location. In addition, intratumoral hemorrhage is often accompanied by edema and enhancement early in its course, and evolution of the hematoma is delayed.

Chou and Singhal described multifocal punctuate intraparenchymal hemorrhages in a patient with blast crisis from acute myeloid leukemia (25). Subdural hemorrhage can be detected on CT or MRI scans, which may also reveal skull or dural tumors if these underlie the hemorrhage. CT scans can initially be normal in patients subsequently shown to have subdural hematoma due to a coagulation disorder (51). Dural enhancement on neuroimaging studies is suggestive, but not diagnostic, of dural tumors. Neoplastic subdural hemorrhage is usually acute but when chronic, it can be difficult to distinguish on neuroimaging studies from effusion of dural tumor.

In patients who experience cerebral infarction, the CT or MRI scan may show single or multiple lesions, depending on the etiology. Some infarctions are hemorrhagic because of an associated coagulation disorder or because the infarction is due to an arterial embolus or venous occlusion. Diffusion-weighted MRI in cerebral infarction from nonbacterial thrombotic endocarditis typically shows numerous infarctions of varying sizes in multiple territories (121). Serial CT and MRI scans can reveal abnormalities additional to infarction, such as contrast-enhancing lesions in evolving abscesses in patients with septic embolic infarction, tumor growth following tumor embolic infarction, and granulomatous angiitis. Gabelmann and colleagues reviewed the MRI findings in nine patients with CNS aspergillosis (41). Single or multiple abscesses were seen in four patients, and four patients had single or multiple infarctions. Each area of infarction was positive on diffusion-weighted imaging. A dural or vascular infiltration pattern was also observed in patients with infection extending from the paranasal sinuses or orbital region. One patient developed a mycotic aneurysm of the internal carotid artery. Computerized axial tomography or MRI scans in PRES associated with chemotherapy typically show edema in the parietal or occipital regions, but edema may be seen in other regions as well (06). The incidence of atrial fibrillation is higher in patients with active cancer; therefore, prolonged cardiac monitoring is reasonable for embolic stroke of undetermined source (ESUS). Based on recent studies, the diagnostic yield is likely to increase with implantable devices.

MRI is the test of choice to detect cerebral venous sinus occlusion. However, if venous flow is slow or if the occlusion is acute, the signal intensity can be difficult to interpret, and magnetic resonance venography is diagnostic (110). MRI and CT scans can also detect skull or dural tumors associated with the metastatic variety of superior sagittal sinus occlusion.

Cerebral angiography is useful in detecting several diseases that cause hemorrhage or ischemia. Cerebral angiography is a sensitive test for detecting vascular occlusions in patients with focal cerebral symptoms from nonbacterial thrombotic endocarditis. Typically, multiple branch occlusions of the middle cerebral artery are found (111). It can facilitate the diagnosis of reversible vasoconstriction syndrome and cerebral venous thrombus. For selected patients, intravenous thrombectomy could recanalize cerebral venous sinus and significantly improve venous return. In leptomeningeal metastasis, angiography may be normal or show focal narrowing of arterioles at the base of brain or over the cerebral convexities.

The sensitivity of angiography in cerebral intravascular coagulation is not known. Angiography in radiation-induced atherosclerosis typically reveals occlusion or extensive stenosis of the common carotid artery confined to the field of radiation (88). In patients with granulomatous angiitis, angiography may be normal or may show typical changes of vasculitis. The sensitivity of angiography in detecting neoplastic aneurysms is not known.

CSF examination is rarely helpful in patients with cancer who experience cerebrovascular complications, though this may change in the near future. In suspected septic fungal infarction, the CSF is usually normal or nonspecifically abnormal. CSF examination may show mildly elevated protein, decreased or normal glucose, or moderate pleocytosis, but cultures are often negative. The CSF in granulomatous angiitis may reveal pleocytosis and elevated protein. Most patients (75% to 90%) with central nervous system angiitis will have elevated CSF WBCs and protein levels. CSF cytologic examination can be diagnostic in patients with leptomeningeal metastasis, but the yield is imperfect. The advent and wide adoption of next-generation sequencing assays could aid the diagnosis. A study from China examined 27 paired CSF/tumor tissues of glioma patients. Twenty-four CSF samples had detectable circulating tumor DNA with a 91.6% concordance rate with the final diagnosis from tumor tissues (129). Similar results were observed in archival CSF specimens. Somatic variants were detected in 31% of samples from patients without MRI enhancement (96). These studies highlight the potential of this new technique.

Patients suspected of septic infarction should have blood cultures drawn, but these may be normal in fungal sepsis. Patients with suspected aspergillosis should undergo a chest x-ray to look for pulmonary infiltrates, but the x-ray may be normal early in the illness. A chest CT scan may be more sensitive. Transbronchial biopsy should be considered for diagnosis, although it may be contraindicated in cases of thrombocytopenia. Echocardiography should be performed in patients with suspected tumor embolic infarction from an atrial myxoma, septic infarction from infective endocarditis, or infarction associated with nonbacterial thrombotic endocarditis. The valvular lesions of nonbacterial thrombotic endocarditis are generally too small to be detected on standard transthoracic echocardiography, but they can be detected by transesophageal echocardiography. Echocardiography can identify structural risks for paradoxical embolism such as patent foramen ovale. Comprehensive coagulation and hematologic function tests should be performed in patients with a suspected coagulation disorder. Useful tests to diagnose acute disseminated intravascular coagulation include the activated partial thromboplastin time, prothrombin time, D-dimer assay, fibrinogen, platelet count, and peripheral blood smear examination. One large-scale study identified that the hemostatic markers thrombin-antithrombin complex, soluble fibrin monomer, and D-dimer are predictive of acute or chronic disseminated intravascular coagulation (cutoff values differ depending on the tumor type) (127). As clinically indicated, limb venous duplex studies or venography, pulmonary ventilation perfusion scans, and electrocardiograms can be useful in patients with suspected systemic thromboembolic complications.

Histologic examination of the hemorrhage and hematoma wall should be performed in patients who experience a brain hemorrhage from a suspected metastatic tumor when the patient does not have cancer and undergoes surgical intervention. In patients with suspected metastatic subdural hemorrhage, biopsy of the hematoma wall or cytologic examination of the subdural fluid is necessary to establish the diagnosis. Biopsy of contrast-enhancing lesions, visible on CT or MRI, is the most sensitive way to establish the diagnosis of cerebral granulomatous angiitis, although given the irregular nature of the affected tissue it has a low specificity. In patients with suspected tumor embolic infarction, examination of a simultaneous peripheral arterial embolus is the only way to confirm this diagnosis. Visualization of a cardiac tumor on echocardiography strongly suggests the diagnosis. All patients with suspected tumor embolic infarction should undergo follow-up CT or MRI brain scans for evidence of tumor growth. Intravascular lymphomatosis can be identified in brain biopsy, leptomeninges, or an active systemic site of lymphoma.

Stroke patients without classical vascular risk factors are more likely to have co-occurrent cancers and warrant further investigation, even long-term cancer surveillance. A study using data from an institutional registry identified 102 (1.5%) newly diagnosed cancer cases (identified during stroke hospitalization or within the following 12 months) among 6686 patients with acute ischemic stroke (30). In a population-based study from Portugal, investigators found that 8.4% of patients with the first cerebrovascular event (TIA, ischemic, or hemorrhagic stroke) developed cancer during follow-up (up to 8 years), and cancer incidence is notably higher in younger age group with RR 3.2 compared to the general population (126). Similar observations have been seen in another study from Asian population in Singapore, and the age-standardized cancer incidence was 15 times higher in ischemic stroke patients (133). The accelerated development of artificial intelligence and machine learning could soon become a valuable weapon in our arsenal. A group of researchers from South Korea analyzed histopathologic images of thrombi obtained through thrombectomy with machine learning models. The platelet model demonstrated consistently high accuracy in classifying patients with cancer and predicted the presence of occult cancer with high probabilities ranging from 88.5% to 99.2% (55).

Management

The therapy for cerebrovascular disorders associated with cancer is largely empiric. No controlled studies have been reported, aside from the management of leukemia complicated by hyperleukocytosis or disseminated intravascular coagulation. Therapy of hemorrhagic brain metastasis should be directed to the underlying brain tumor(s), typically radiation therapy. This is often delayed until after the acute issues are controlled. There are no solid arguments for emergent radiation in this setting. Some patients with a single neoplastic hemorrhage benefit from surgical removal. Patients who have systemic cancer resulting in a neoplastic aneurysm should undergo aggressive therapy of the tumor to prevent subsequent tumor embolization. Multiple intracranial aneurysms could occur in a delayed fashion months after resection of cardiac myxoma (128). Depending on presenting symptoms and following clinical conditions, a combination of observation, open surgery, coiling, radiation, and chemotherapy could be selected. Subdural hemorrhage caused by dural metastasis should be treated with drainage of the subdural fluid, if it is symptomatic, and brain radiation. Patients who develop cerebral hemorrhage from a coagulation disorder should be treated with replacement of blood clotting factors, platelets, heparin, and antiedema measures, as indicated. Most patients with subdural hematoma caused by a coagulopathy can be successfully treated without surgery (51; 28). The therapy for treatment-related cerebral hemorrhages is the discontinuation of the offending drug. The treatment of microangiopathic hemolytic anemia syndrome is based on the use of antihypertensives and immunocomplex removal techniques, including exchange transfusion, plasmapheresis, and immunoadsorption (48). The effect of immunosuppressive agents, including corticosteroids, is uncertain. In cases where the thrombotic microangiopathy is secondary to the use of antitumoral drugs, the offending agent should also be discontinued.

Intravenous thrombolysis and endovascular recanalization are the mainstays of treatment for patients with acute ischemic stroke. However, these approaches have not been studied prospectively in individuals with associated malignancies. Data obtained in nonrandomized studies have shown that the efficacy and safety of thrombolytic agents are similar for patients with or without cancer (57; 101). Thus, the 2019 American Heart Association Guidelines for the treatment of acute ischemic stroke indicate that, with the exception of gastrointestinal malignancy, patients with acute ischemic stroke and cancer who have a reasonable (longer than> 6 months) life expectancy should be considered for treatment with intravenous thrombolysis provided that they do not have other contraindications (108). Similarly, the results from observational studies suggest that endovascular recanalization is beneficial for the treatment of patients with large vessel occlusion and cancer (23; 04; 117; 116). Thus, a history of malignancy, in and of itself, should not be considered an absolute contraindication for endovascular recanalization in patients with large vessel occlusion.

The management of systemic and cerebral thromboembolic disorders caused by activated coagulation in cancer patients is controversial. When treating cancer-associated venous thromboembolism, low molecular weight heparin may be more effective than warfarin. In a randomized trial of cancer patients with systemic venous thromboembolism, a 50% relative risk reduction in recurrent thromboembolism was observed in favor of low molecular weight heparin compared to warfarin (70). In the past few years, more studies have compared direct oral anticoagulants to low molecular weight heparin due to the convenience of direct oral anticoagulants administration. In a study done in patients with cancer-associated venous thromboembolism, the direct factor Xa inhibitor apixaban was associated with a similar risk of major bleeding but a lower rate of recurrent venous thromboembolism than dalteparin (0.7% vs. 6.3%; P = 0.03) (84). In another study of 576 patients with cancer, apixaban was not inferior to dalteparin for the prevention of recurrent venous thromboembolism (02). A randomized clinical trial (RCT) enrolled a total of 671 patients and showed that direct oral anticoagulants were noninferior to low molecular weight heparin for preventing recurrent venous thromboembolism over six-month follow-up (114). The results of a meta-analysis of 15 randomized controlled trials that compared different combinations of direct oral anticoagulants, low molecular weight heparin, and warfarin for the prevention and treatment of venous thromboembolism in patients with cancer demonstrated that apixaban has the lowest risk of venous thromboembolism occurrence and major hemorrhage, whereas low molecular weight heparin has the lowest risk of clinically relevant nonmajor hemorrhage (131). Several clinical guidelines endorse the use of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism with consideration of renal function, gastrointestinal absorption impairment, and drug-drug interactions (39; 78). The combination of low molecular weight heparin and warfarin is commonly used for cerebral venous thromboembolism (124). In a systematic review of 33 studies, the risk of cerebral venous thromboembolism–associated death, new intracranial hemorrhage, and favorable outcome was comparable for patients treated with warfarin or direct oral anticoagulants (10). However, it is unclear if these results can be extrapolated to patients with cancer-associated cerebral venous thromboembolism.

The prevention of recurrent stroke in cancer patients is debatable. For newly diagnosed cancer individuals, prior ischemic stroke increases the risk (aHR, 2.68 [95% CI, 2.41-2.98]) of ischemic stroke after cancer diagnosis (79). Patient with active cancer has an elevated risk of atrial fibrillation, with the highest incidence found in multiple myeloma (135). Meanwhile, a study has reported that exposure to anticoagulation increased the risk of major bleeding events compared to exposure to antiplatelet for patients with cancer-related stroke (24). Direct oral anticoagulants were recommended for secondary stroke prevention in patients with nonvalvular atrial fibrillation and cancer (66), but stage and type of cancer, frailty, excess body weight, and kidney function should be taken into consideration. Approximately 50% of strokes in patients with cancer are cryptogenic. Owing to the procoagulable state associated with malignancies and based on the data obtained in venous thromboembolism trials, low molecular weight heparin is commonly used for patients with cancer-associated embolic stroke of undetermined source (ESUS). However, two randomized studies of noncancer patients failed to demonstrate the superiority of direct oral anticoagulants over aspirin for ESUS (53; 33). Currently, the superiority of anticoagulation over antiplatelet agents for patients with cancer-associated ESUS has not been demonstrated (66; 43).

Patients with cardiac myxoma should undergo the removal of the cardiac tumor. Patients with metastatic venous occlusion should be treated with brain radiation. Also, those with fungal sepsis and embolic infarction should be treated with antifungal therapy, although it rarely successfully eradicates the infection. The treatment for radiation-induced carotid artery disease is disputable. Surgical revascularization is as effective and safe as in nonirradiated patients (73), despite restenosis risks. Angioplasty and stent placement are effective (03) with a low rate of complication and restenosis (52). A direct comparison with surgery has not been performed. The proper method to treat the stenosis should be evaluated after careful screening for recurrent malignancy, as the major risk for death in a clinical cohort was underlying cancer (81). Low-dose heparin administration may reduce the risk of cerebral infarction in patients undergoing ligation to treat carotid rupture. Various endovascular techniques can be used to treat threatened or acute carotid blowout syndrome (19). Intravascular lymphomatosis should be aggressively treated with steroids and chemotherapy, with or without brain radiation (107). Leptomeningeal metastasis may be treated with radiation, systemic therapy, intraventricular chemotherapy, or a combination of these approaches. Granulomatous angiitis can respond to successful therapy of the associated Hodgkin disease or leukemia or to cytotoxic drugs administered for the vasculitis.