Fig. 10.1
a Brain coronal section demonstrating a glioblastoma with necrosis and intratumoral hemorrhage, centered within the right anterior frontal white matter. There is prominent mass effect. b Microscopic image in this patient at autopsy reveals fibrillary and giant cells, with intervening areas of hemorrhage (H&E ×200)
The most common clinical symptoms in patients with intratumoral hemorrhage are headache, nausea, vomiting, obtundation, seizures, and focal neurologic deficits, similar to hemorrhages of other etiology. The symptoms may be acute or subacute. Bleeding may be spontaneous or associated with predisposing factors such as head trauma, hypertension, coagulopathy, shunting procedures, surgery, and anticoagulation [3]. Various pathophysiologic processes unique to the tumor also contribute to intratumoral hemorrhage, including overexpression of vascular endothelial growth factor and matrix metalloproteinases, endothelial proliferation, rapid tumor growth, vessel necrosis, and compression or invasion of adjacent parenchymal vessel walls by tumor [14, 15].
Imaging findings on brain CT or MR scan that suggest neoplastic hemorrhage include early edema, an indentation appearing on the hematoma surface that enhances with administration of contrast, delayed hemorrhage evolution and early perihemorrhage enhancement [16, 17].
Treatment is directed to the underlying tumor and may include surgical resection followed by radiation therapy and medical therapies appropriate to the histology. Patient outcome after intratumoral hemorrhage is related to the specific histological malignancy of the tumor and extent of the systemic cancer. There appears to be a higher risk of recurrent hemorrhage if the tumor is incompletely excised or if metastases recur.
Hemorrhage into pituitary adenomas (pituitary apoplexy) is a unique and rare disorder, often accompanied by infarction of the pituitary gland. It can be life-threatening because of corticotropin and thyroid hormone deficiency. The most common presenting symptom is headache, followed by visual field abnormalities and cranial nerve palsies. MRI is superior to CT in establishing the diagnosis. MRI typically shows an intra-and suprasellar expanding mass with T1 and T2 signal intensities consistent with the evolution of blood products. Enhancement is usually faint. Thickening of the sphenoid sinus mucosa is highly indicative of pituitary apoplexy [18].
A recent retrospective review from the Mayo Clinic identified 87 cases of pituitary apoplexy, mostly male, with a mean age of 51 years. Only 25% had a known pituitary adenoma. The most common associated factor was hypertension (39%). Long-term outcome was good, although most patients required long-term hormonal placement [19]. There are no controlled studies to prove a benefit of surgical decompression; observation, with replacement of hormones as clinically indicated, is appropriate in many patients.
Neoplastic Subdural Hemorrhage
Subdural hematomas and hygromas are common etiologies for cerebrovascular disease in cancer patients, comprising 12.6% of all strokes and 25.8% of hemorrhagic lesions identified at autopsy within this population [1]. Overall, subdural hemorrhages related to dural metastasis are less common than those related to coagulopathy or trauma in cancer patients [20]. Neoplastic subdural hemorrhages occur more commonly in patients with solid, rather than hematological tumors, and in particular with tumors metastatic from prostate, lung, or breast cancer primaries [20, 21].
Neoplastic infiltration of the dura results from hematogenous spread of tumor into the dural vessels or from direct extension of skull metastasis. Proposed mechanisms for the occurrence of subdural hematoma with dural metastasis include hemorrhage directly into the dural tumor, hemorrhage secondary to dilatation and rupture of the inner dural capillaries/venules/veins due to outer vessel layer obstruction by tumor, and in rare cases, dural tumor production of a hemorrhagic effusion.
Acute and subacute subdural hemorrhages are more common than are chronic. Graus et al. [1] reported that one-quarter of their 53 autopsied subdural hematoma patients with cancer were symptomatic. Clinical manifestations in the oncologic population differ little from the general population. The most common clinical symptoms are altered mental status, headache, and lethargy. Focal neurological deficits and seizures may also be present.
Acute or chronic subdural hematomas and skull metastases are generally easily visualized with both CT and MRI. Contrast studies are helpful in revealing skull or dural enhancement. Histologic examination of the dura with biopsy or cytologic studies of the subdural fluid may be necessary to confirm the tumoral origin of the subdural hematoma. Figure 10.2a–c shows the imaging and subdural fluid cytology findings in a patient with dural metastasis from lung cancer [22].
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Fig. 10.2
a Brain magnetic resonance image taken on admission shows bilateral masses in the brain. b Brain magnetic resonance image taken on deterioration of symptoms shows bilateral crescent-shaped isointensity lesions and a shrunken brain mass. c Adenocarcinoma cells detected in hematoma fluid (All Used with permission of Elsevier from Hata et al. [22])
Treatment of dural metastasis-associated hemorrhage is palliative and includes drainage of subdural fluid and radiation therapy.
Neoplastic Infiltration of Cerebral Vessels
Venous Infiltration
Thrombosis of cerebral veins or dural sinuses is a rare event in any patient population, including those with cancer. Cerebral venous thrombosis accounted was diagnosed in only 0.3% of neurological consultations in cancer patients over a four year period at Memorial Sloan-Kettering Cancer Center [23].
The most common cause of cerebral venous thrombosis in cancer patients is a coagulopathy associated with hematologic tumors. Invasion or compression of dural sinuses or cortical veins by tumor occurs most commonly in solid tumors that are metastatic to the dura, skull, or rarely, the leptomeninges [23, 24].
The most common vein affected by metastasis is the superior sagittal sinus. Headache is the most frequent presenting symptom of venous thrombosis. This may be accompanied by focal neurological deficits, encephalopathy, or seizures when there is adjacent venous infarction. Occasionally patients present with an isolated intracranial hypertension syndrome, with headache that may be accompanied by visual disturbances associated with papilledema or abducens palsy. When due to neoplastic vessel compression or invasion, neurologic symptoms from venous thrombosis often develop subacutely, in contrast to the thrombosis associated with coagulopathy, in which symptom onset is typically acute [23].
Brain CT or MRI scanning with contrast may reveal a lack of contrast within the sagittal sinus because of the thrombosis, a finding known as the “empty delta sign” but this is uncommon. Overall MRI is superior to CT in detecting venous thrombosis. The sensitivity increases with the concomitant use of MRA and MRV. MRI can also demonstrate parenchymal abnormalities of venous infarction or hemorrhage, and identify adjacent tumor.
When venous occlusion is due to tumor compression or infiltration, the clinical course is generally progressive and antineoplastic therapy to treat the tumor may be indicated. Therapeutic options include tumor resection, radiation, or systemic therapy. The use of anticoagulation or thrombolysis has not been studied in this setting.
Arterial Infiltration
Neoplastic infiltration of arterial vessels has been reported to cause both hemorrhagic and ischemic strokes. Cerebral tumor embolization can result in aneurysm or pseudoaneurysm formation and subsequent aneurysm rupture produces intracerebral and/or subarachnoid hemorrhage. A recent literature review of neoplastic cerebral aneurysms identified 96 published cases. Cardiac myxoma was the most common underlying tumor (60%), choriocarcinoma was next most common (26%) and other malignant tumors accounted for 13.5%. Hemorrhage was universal in choriocarcinoma, less common in other malignant tumors (84.6%) and uncommon in myxoma (19.6%) [25]. Figure 10.3a–c shows multiple brain hemorrhages in a patient with ruptured neoplastic pseudoaneurysms associated with metastatic choriocarcinoma. The diagnosis of neoplastic aneurysm can be made by cerebral arteriography. Neoplastic aneurysms are typically small in size and are often located in distal cerebral arterial branches, in contrast to saccular aneurysms which arise in proximal cerebral arteries. Those from cardiac myxoma are usually multiple, whereas those from malignant tumors are usually single. The prognosis is poor in tumors other than cardiac myxoma. A second, less common, mechanism of aneurysm formation is secondary invasion of nearby vessels by parenchymal brain metastases [26].
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Fig. 10.3
Intracerebral hemorrhages due to metastatic choriocarcinoma with pseudoaneurysm formation. a Computed tomography on day 20 shows right frontal (large arrow) and right parietal hemorrhages with extension to the lateral ventricle (small arrows). b Magnetic resonance imaging on day 25 shows a new left posterior frontal hemorrhage (large black arrow) and left parieto-occipito-temporal subdural hematoma (large white arrow) and old right frontal and parietal hemorrhages (small arrows). c Computed tomography on day 29 shows increase in the left frontal hemorrhage and new occipital hemorrhages (large arrows) and old right temporal and parietal hemorrhages (small arrows) (All Used with permission of John Wiley and Sons from Kalafut et al. [131])
Ischemic stroke has also been associated with infiltration of arteries by tumor in the leptomeninges [27, 28]. Patients experiencing ischemia secondary to leptomeningeal metastasis present with abrupt, focal neurological deficits alone or in addition to the typical clinical features of leptomeningeal tumor. Angiography may reveal focal arteriolar narrowing at the base of the brain, over the cerebral convexities, or both. Figure 10.4 demonstrates the angiographic findings in a patient with diffuse leptomeningeal dissemination of glioblastoma. Biopsy showed that leptomeningeal tumor caused vascular narrowing by vessel encasement, vascular wall invasion, and thrombosis [28].
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Fig. 10.4
Digital subtraction angiography of vertebral artery injection performed in the anteroposterior projection shows multiple zones of irregularity and narrowing involving the basilar artery, bilateral posterior cerebral arteries, bilateral superior cerebellar arteries and bilateral anterior inferior cerebellar arteries (Used with permission from Herman et al. [28])
Hematologic Malignancies
Myeloproliferative disorders are acquired clonal disorders characterized by the proliferation of bone marrow myeloid cells. Among these, polycythemia vera and essential thrombocythemia are the most common to be associated with systemic and neurologic thrombotic complications, including cerebral infarction, TIA and venous thrombosis. Risk factors for thrombosis include those associated with the underlying disease, including increased white blood cell counts, vascular cell activation, endothelial dysfunction, and plasmatic risk factors, such as increased plasma viscosity, reduced levels of protein S, increased thrombin generation and standard stroke risk factors such as increased age, previous thrombotic events, smoking, hypertension, diabetes, dyslipidemia and obesity for arterial events. Oral contraceptives and pregnancy/puerperium) may contribute to venous thrombosis. Primary prevention includes antiplatelet therapy for arterial thrombosis and anticoagulation for venous thrombosis [29]. Of interest, cerebral thromboembolic complications frequently occur during the two years preceding the diagnosis of a myeloproliferative disorder [30]. Cytoreductive treatment of blood hyperviscosity by phlebotomy or chemotherapy substantially reduces thrombotic events and improves survival.
Hyperleukocytosis (>100,000 WBC/mm3) is a rare presentation of acute lymphoblastic leukemia (ALL) . It can also occur in patients with acute and chronic myelogenous leukemias. It typically occurs during blast crisis and results in leukostasis, the plugging of blood vessels by blasts, most commonly in the lung and brain. Coalescence of cells forms leukemic nodules and can be complicated by brain hemorrhage, typically located in the white matter. Clinical signs include focal neurologic deficits and encephalopathy. Brain MRI findings in hyperleukocytosis are rarely reported; one well-characterized case demonstrated multiple hemorrhages and nonhemorrhagic changes on T1- and T2-weighted images with delayed enhancement and restricted diffusion [31]. It is rapidly fatal if not treated. Emergency treatments include hydration, cytoreduction, prevention of tumor lysis, leukapheresis and brain radiation therapy [32, 33].
Intravascular lymphomatosis (IVL) is a rare variant of non-Hodgkin’s lymphoma characterized by a proliferation of lymphoma cells within small caliber blood vessels, with a predilection for the skin and CNS. Figure 10.5 is a brain biopsy depiction of IVL pathology. IVL patients with neurologic involvement most commonly present with subacute progressive multifocal cerebral infarcts and/or a rapidly progressive encephalopathy accompanied by fever. Other sites, such as lung, spleen, and bone marrow may also be involved. In a meta-analysis of the literature between 1962 and 2011, Fonkem et al. [34] identified 740 published cases. The median age was 64 years. The majority (88%) were of B cell origin.
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Fig. 10.5
Brain biopsy in a patient with confusion and multiple enhancing parenchymal lesions on brain MRI reveals intravascular lymphoma (H&E ×400)
Brain MRI typically demonstrates multiple lesions, most commonly in the cerebral hemispheres. Early diffusion changes that follow the typical time course noted in ischemic events can be observed. Noninvasive and catheter angiography may demonstrate a vasculitis-like appearance [35]. Because the diagnosis is difficult to establish from clinical symptoms, there is often a delay in diagnosis or lack of diagnosis during life. Historically, the majority of cases have been diagnosed postmortem. The most effective therapy is not known, but reports indicate that chemotherapy and rituximab or radiotherapy can stabilize the clinical course.
Tumor Embolus
Ischemic stroke secondary to tumor embolism is rare. In the series by Graus et al. [1] only two patients had tumor emboli identified as the etiology of infarction. Most reported cases of tumor embolic stroke result from intracardiac tumors. The majority of the tumors arise from the left side of the heart. They are most often benign. In a large recent series of resected primary cardiac tumors, myxoma was the most common histology (72.6%). Fibromas and sarcomas were rare, 6.9 and 6.4% respectively. Ten percent of patients with intracardiac tumor experienced a stroke [36].
Cerebral TIA or infarction may also occur from tumor emboli arising from tumors metastatic to the heart. Cardiac metastasis usually occurs in the presence of widely metastatic disease. In an autopsy study of 95 patient with cardiac metastases, the underlying cancers, in descending order, were of lung, lymphoma, breast, leukemia, gastric, melanoma, liver and colon origin [37, 38]. Figure 10.6a–d shows the head CT, echocardiography and brain pathology of cerebral embolism from a cardiac metastatic tumor.
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Fig. 10.6
Imaging and histologic findings in a patient with multifocal stroke from tumor emboli. a Head computed tomography demonstrating a left frontal lobe hypodensity consistent with middle cerebral artery territory infarction. b Transthoracic echocardiogram with apical 3-chamber view showing 2 large mobile echodensities attached to the septum and inferolateral wall of the left ventricle (V). c Frontal lobe arteriole occluded by moderately differentiated squamous cell carcinoma. Recent infarction is present surrounding the embolus, with disintegration, vacuolization, and pyknosis of neurons (hematoxylin-eosin, original magnification ×20). d Tumor embolus of squamous cell carcinoma occluding a cerebellar vessel. Small areas of infarction surround the embolus, with proliferation of capillaries and macrophages (hematoxylin-eosin, original magnification ×40) (All Used with permission of American Medical Association from Navi et al. [38]. All rights reserved)
As in other embolic strokes, neurological symptoms are typically sudden and infarction may be preceded by TIA. History and physical examination findings of cardiac dysfunction such as limb edema, dyspnea, arrhythmias, peripheral vascular emboli, and precordial murmurs are helpful in identifying a cardiac tumor. Echocardiography is a reliable means of diagnosing cardiac tumors and may suggest the histology. Transesophageal echocardiogram is superior to transthoracic echocardiography in evaluating atrial tumors. False negative echocardiograms have been reported in cardiac neoplasm patients; cardiac MRI and CT can be useful in this situation. Tissue diagnosis involves obtaining a pathological specimen through endomyocardial biopsy or surgical resection of the tumor.
Primary or metastatic lung cancers can also produce TIA or cerebral infarction from a tumor embolus that accesses the pulmonary venous system and then passes through the left heart chambers to the cerebral vasculature. Cerebral infarction that is identified in the peri-operative period after lung cancer biopsy or resection should suggest embolization of a tumor fragment [39]. Patients with tumor embolic ischemia should be followed with surveillance brain imaging to observe for tumor growth.
Stroke Due to Remote Effects of Tumor: Hyper- and Hypocoagulopathies
Hypercoagulability and Thrombosis
Abnormalities of the coagulation system are very common in the cancer patient, and there is a high propensity for thrombosis of venous or arterial vessels, especially in widely disseminated solid tumors and in glioblastoma. Venous thromboembolism (VTE) and disseminated intravascular coagulation complicate the course in a significant percentage of patients, depending on the histology. Increases of coagulation factors V, VIII, IX, and XI are often documented in malignancy. Markers of coagulation activation are frequently elevated, including prothrombin fragment 1.2, thrombin antithrombin complex, fibrin degradation products, and D-dimers. Also consistent with a consumptive coagulopathy is the frequent finding of increased fibrinogen and platelet turnover.
Schwarzbach et al. [40] documented the presence of hypercoagulation as a cause of stroke in cancer patients, especially those with significantly elevated D-dimer levels, as compared with controls, and in the absence of conventional stroke risk factors. A hypercoagulable state can result in intravascular thrombosis as well as sterile platelet-fibrin deposition on cardiac valves termed nonbacterial thrombotic endocarditis (NBTE). In comparing the sensitivity of transthoracic and transesophageal echocardiograms, a retrospective review of 654 consecutive cancer patients in whom infectious or noninfectious endocarditis was suspected confirmed the diagnosis of endocarditis in 45 patients (75%). TEE was significantly more sensitive in detecting endocarditis: in 21 of 22 cases, TEE examinations were diagnostic and 16 (42%) of 38 patients with initially nondiagnostic TTE studies had the diagnosis confirmed by TEE study. Vegetations were larger in patients with culture positive endocarditis than in patients without culture positive infection [41].
In a study to determine the frequency of cardioembolic findings in 51 consecutive patients with cancer referred for TEE evaluation of cerebrovascular events, 18% had NBTE and 47 and 55% had definite and definite or probable cardiac sources of embolism, respectively [42]. Singhal et al. [43] compared the MRI findings in patients with infectious endocarditis and NBTE. Patients with NBTE uniformly had multiple, widely distributed, small (<10 mm) and large (>30 mm) infarctions (Fig. 10.7a–c), whereas patients with infectious endocarditis had a variety of stroke patterns including a single lesion, territorial infarction, and disseminated punctate lesions, and numerous small, medium or large lesions in multiple territories.
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Fig. 10.7
a Initial DWI in a patient with infective endocarditis shows disseminated punctate ischemic lesions (pattern 3). Note the incidental ventricular hyperintensity (arrow), suggestive of ventriculitis. b Follow-up DWI after 1 week shows additional punctate lesions but no change in the stroke pattern. c Initial DWI in a patient with nonbacterial thrombotic endocarditis shows multiple small and large lesions (pattern 4) (All Used with permission from Singhal et al. [43])
Venous Occlusions
Cerebral venous thrombosis can occur from direct tumor invasion or compression of the dural sinuses (reviewed above), but more commonly occurs from a hypercoagulable state induced by a neoplasm or chemotherapy. A systemic coagulopathy is the most common cause of cerebral venous thrombosis in patients with hematologic malignancies, especially ALL or lymphoma after treatment with l-asparaginase [23]. Steroids may contribute to the development of thrombosis.
The clinical presentation is similar to patients without cancer who develop sinus thrombosis, and includes headache, vomiting, papilledema, and seizures. Focal neurological signs or encephalopathy may also occur if there is associated cerebral infarction or hemorrhage. Imaging characteristics are reviewed above, but in the instance of coagulation-related venous thrombosis, no skull or dural tumor is identified [44]. Spontaneous resolution or recanalization of nonmetastatic sinus thrombosis can occur, especially early in the course of cancer and its treatment. When the thrombus is symptomatic and persistent, treatment should be considered. Two randomized clinical trials have studied the benefits and risks of anticoagulation in patients without cancer who develop sinus thrombosis. A small trial of intravenous unfractionated heparin found a benefit; a larger trial of low molecular weight heparin found only a nonsignificant trend to benefit [45, 46]. The safety of anticoagulation in ALL patients has been reported in small numbers of patients [47, 48]. Small series also document the benefit of endovascular thrombectomy and thrombolysis [49, 50]. The safety and efficacy of these latter treatments in the cancer population has not been established.
Arterial Occlusions
Cerebral arterial occlusions constitute a major source of morbidity in cancer patients. The most common cause for thrombotic arterial occlusions in cancer-associated thrombophilia is NBTE (see above) Vegetations are most commonly located on the aortic and mitral valves. NBTE is significantly more common in cancer patients than in patients without malignancy; it occurs most commonly in adenocarcinoma patients, especially pancreatic cancer [51, 52]. Mucin-producing adenocarcinomas, of which many are pancreatic, are strongly associated with NBTE [53]. Rarely, NBTE is the presenting sign of cancer.
The mechanism of cerebral TIA or infarction in NBTE is small vessel thrombosis as a result of intravascular thrombosis or embolization of a sterile vegetation to brain vessels [54]. Systemic thromboembolism, both venous and arterial, may be a clue to NBTE in a cancer patient with cerebral ischemia. However, one-third of patients have only neurologic symptomatology [52]. The diagnosis may be difficult to suspect on clinical grounds alone, because NBTE can result in signs of encephalopathy caused by multiple small vascular thrombosis. In other patients, sudden focal neurological symptoms of TIA or stroke suggest embolization. The majority of patients with NBTE have only mildly abnormal coagulation parameters. The diagnosis of NBTE is most often rendered in vivo by echocardiographic detection of valvular vegetations. Transesophageal echocardiography is more sensitive than transthoracic. Both neuroimaging and autopsy studies show that cerebral infarcts may be multiple and sometimes have a hemorrhagic component. Cerebral angiography typically discloses multiple vessel branch occlusions, commonly in the middle cerebral artery territory [52].
Appropriate treatment of NBTE includes treatment directed to the underlying cause for the coagulation disorder, such as the neoplasm or sepsis if this coexists. There are no prospective studies of anticoagulation in NBTE; however, individual case reports and retrospective cases series suggest that anticoagulation with heparin appears to reduce ischemic symptomatology in some patients [52]. The potential benefits of anticoagulation should be weighed cautiously against the potential risks of hemorrhage in the cancer patient with NBTE-associated stroke.
Mucin-Positive Adenocarcinoma-Associated Hypercoaguability
Mucin-producing adenocarcinomas are associated with arterial ischemic stroke both in association with, and independently of, NBTE. A 1989 study examined patients with mucinous adenocarcinoma and systemic and cerebral ischemia [55]. Widely disseminated metastases were present in all cases. Varying sizes of cerebral infarctions were found, including disseminated microinfarcts in all patients and large or small/moderate sized infarcts in most. Ischemia affected widespread areas of the CNS, including the cerebral hemispheres, cerebellum, brainstem, basal ganglia, spinal cord, and dorsal spinal roots. Petechial and small hemorrhages were also relatively common. In each of the cases in this series, intravascular mucin was noted within central nervous system capillaries and small arteries on pathological examination.
The mechanism of hypercoagulability in mucin-secreting adenocarcinoma is still not fully understood. Mucin itself may be prothrombotic, the mucin-producing tumor cells may be prothrombotic, or both [56]. There may also be fat emboli in association with mucin [57]. At present, the diagnosis of mucin-positivity is only reliably made pathologically, typically at autopsy. Treatment of the underlying malignancy is the only known method to reduce further cerebrovascular events. Cautious anticoagulation has been suggested in the setting of ischemic stroke and mucin-positive neoplasm, but this therapy is unproven. Figure 10.8 shows multifocal bilateral ischemia visualized on MRI in two patients with breast cancer in whom intravascular mucin was identified pathologically.
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Fig. 10.8
MRI, focal T2 hyperintensities involving all lobes in Case 1, most prominently left occipital lobe in Case 2 (All Used with permission of Springer Science from Bernardo et al. [56])
Combined Hypercoaguability/Bleeding Diathesis
Normal physiologic hemostasis involves a balance between thrombus formation and thrombolysis [58]. Disseminated intravascular coagulation (DIC) is characterized by widespread activation of coagulation, with resulting production of fibrin clot formation and thrombotic occlusion of small and medium size vessels. Formation of thrombi leads to consumption of endogenous coagulation factors, platelets, and anticoagulant factors such as Protein S, Protein C, and antithrombin, increasing a risk for bleeding [59]. Acute DIC is most commonly observed in acute promyelocytic leukemia (APML) because of a unique constellation of factors associated with the leukocytes [60]. Other risk factors for acute DIC are pancreatic and other mucin-producing solid tumors, age >60 years, male gender, breast cancer, tumor necrosis, and advanced stage disease [61]. Patients may present with symptoms and signs of excessive hypercoaguability, uncontrolled hemorrhage, or both simultaneously. In aPML, brain hemorrhage is often fatal. Acute, or uncompensated, DIC occurs most frequently with hematogenous malignancies such as the acute leukemias, and is less frequent with solid tumors. Acute DIC typically presents with clinically significant bleeding with concomitant thrombosis. Bleeding from venipuncture sites and surgical wounds may be seen, as well as diffuse mucosal, skin, or retroperitoneal hemorrhage. Central nervous system hemorrhage is a significant and potentially fatal complication, especially in acute promyelocytic leukemia (APML) Laboratory findings in acute DIC include thrombocytopenia, prolonged PT and aPTT, low fibrinogen, elevated D dimer and microangiopathic changes on the peripheral blood smear.
Chronic DIC develops when blood is continuously or intermittently exposed to smaller amounts of procoagulant substances. The coagulation factors and platelets are consumers, but production is able to compensate. Thrombosis generally predominates over bleeding. Chronic DIC more often manifests as thrombosis, rather than bleeding, although either or both hematologic dyscrasias are possible. Chronic DIC has been reported in the clinical settings of NBTE and mucin-positive adenocarcinoma-associated thrombosis. Patients in chronic DIC typically present with deep venous thrombosis and pulmonary thromboembolism, although some may also develop arterial ischemia. Coagulation tests may be normal or show mild thrombocytopenia, mild prolongation of PT and aPTT, and normal or slightly elevated fibrinogen. D dimer is often elevated.
No prospective clinical trials address the optimal treatment for chronic or acute DIC associated with symptomatic cerebral thrombosis or hemorrhage. Treatment of the cancer is fundamental to successful long-term therapy. Anticoagulants, by interrupting the coagulation cascade, are of theoretical benefit. Unfractionated and low molecular weight heparins have appeared beneficial in small, uncontrolled cohorts but have not been definitively evaluated in controlled clinical trials [62]. Direct thrombin inhibitors are promising but unvalidated in controlled trials [59].
Bleeding Diathesis/Hemorrhage
Primary Fibrinolysis
Primary fibrinolysis is characterized by systemic activation of plasmin or direct fibrinogen degradation. Intracranial hemorrhage may result from primary fibrinolysis in association with acute DIC early in the course of APML. Primary fibrinolysis, without DIC, has been observed in some leukemias and solid tumors, especially prostate cancer. Cerebrovascular complications are rare in this setting. Treatment consists of administering cryoprecipitate or fresh frozen plasma. Epsilon-aminocaproic acid or tranexamic acid may also be given [63].
Thrombocytopenia
Thrombocytopenia is not uncommon in the cancer population and poses a risk for intracranial hemorrhage Thrombocytopenia-associated cerebral hemorrhage in oncology patients can be secondary to extensive marrow infiltration by tumor, peripheral destruction of platelets due to tumor-associated hypersplenism, under-production of platelets due to radiation- or chemotherapy-induced toxicity, DIC, autoimmune dysfunction, and/or microangiopathic hemolytic anemia. Cancer-associated hemolytic anemia is a Coombs-negative hemolytic anemia. A review of published cases published in 2012 reported 154 cases associated with solid cancer and 14 cases with lymphoma. The majority of the cancers were metastatic. The prognosis is poor. Treatment includes antitumor treatment and plasma exchange or fresh frozen plasma; the latter was rarely effective, except in prostate cancer patients [64].
Immune-mediated peripheral platelet destruction is rarely seen with solid tumors, but has been reported with lymphoproliferative disorders such as Hodgkin’s disease, chronic lymphocytic leukemia, and low-grade lymphoma [65]. Diagnosis is difficult but may be supported by the acute onset of thrombocytopenia, large platelet size, elevated megakaryocyte count, and increased platelet-associated immunoglobulin. Treatment may include corticosteroids, immunoglobulin infusions, plasmapheresis, antineoplastic therapy directed at the specific underlying malignancy, vincristine, danazol, and immunoabsorption with staphylococcal protein A.
Thrombotic thrombocytopenic purpura (TTP) is a syndrome of target organ dysfunction due to marked platelet aggregation in the microcirculation that can be induced both by cancer and by chemotherapeutic treatment [66]. Thrombotic thrombocytopenic purpura is characterized by severe thrombocytopenia, a microangiopathic hemolytic anemia, and renal failure (hemolytic-uremic syndrome) Intracerebral hemorrhage and cerebral infarction are potentially disastrous events that may complicate the course of patients with TTP. Platelet aggregates in TTP most commonly occlude the arterioles and capillaries in the brain, heart, kidneys, and adrenal glands. Clinically, purpuric rash, fever, and neurological and renal symptoms are common. Laboratory studies demonstrate severe hemolytic anemia, thrombocytopenia, and schistocytosis. Thrombotic thrombocytopenic purpura can be differentiated from DIC by the absence of a coagulopathy. In cancer patients, TTP is most commonly seen with gastric adenocarcinoma, followed by breast, colon, and small cell lung carcinoma. Treatment options include corticosteroids, plasma exchange, immunoabsorption with staphylococcal protein A, platelet inhibitor drugs, vincristine, and splenectomy. Platelet transfusions are reserved for situations of documented bleeding. Mortality in TTP without treatment is 90–100%. With appropriate treatment, mortality decreases to 10%.
Sequelae of Cancer Treatment
In addition to cancer and its associated coagulopathies as a cause of stroke, ischemic or hemorrhagic strokes can result from certain diagnostic procedures, radiation therapy, surgical therapy, endovascular treatments, or chemotherapy.
Cancer Therapy: Radiation
Radiation-Induced Vasculopathy
A variety of delayed vasculopathies can complicate therapeutic radiation to the brain or neck. Pathologic studies demonstrate that radiotherapy produces a sequence of vascular changes characterized by initial damage to endothelial cells, followed by thickening of the intimal layer, cellular degeneration, and hyaline transformation. Stenosis and occlusion of medium and large vessels leading to ischemic infarction is the most common sequela, but lacunar infarction, primary intracerebral hemorrhage, moyamoya changes resulting in ischemia or hemorrhage, and the formation of cerebral aneurysms and pseudoaneurysms also occur [67, 68].
Several large scale studies, particularly those from the Childrens Cancer Study Group (CCSG) describe the risk of stroke in pediatric cancer survivors (alive > five years), especially those with brain tumors and those with leukemia who received cranial radiation therapy. The rate of first occurrence of late-occurring stroke was determined in leukemia (n = 4828) and brain tumor survivors (n = 1871) as compared with a group of a random sample of cancer survivor siblings (n = 3846). The rate for leukemia survivors was 57.9 per 100,000 person-years and the relative risk for stroke, as compared with the sibling comparison group, was 6.4. In brain tumor survivors, the rate was 267.6 per 100,000 person-years and the relative risk was 29. Mean cranial radiation therapy dose >30 Gy was associated with an increased risk in both leukemia and brain tumor survivors in a dose-dependent fashion, with the highest risk after doses of >50 Gy [69].
The CCSG also recently identified that among childhood cancer survivors with stroke, there is a risk of recurrent stroke, especially those receiving >50 Gy cranial radiation therapy. The risk persists for decades after the first stroke: the ten-year cumulative incidence of late recurrent stroke was 21% overall and 33% for those treated with high dose cranial radiation therapy. Hypertension also independently predicted recurrent stroke in this population [70].
Single institution studies also confirm and characterize the risk of stroke in survivors of pediatric brain tumors and that location of tumor influences the risk. Multivariate and logistic regression analysis in one study showed that children treated with cranial radiation therapy and those with optic pathway gliomas had the highest risk of nonperioperative stroke [71]. Treatment of tumors close to the circle of Willis, especially optic pathway gliomas and the prepontine cistern, were associated with the highest risk in another study [72]. Location of tumor is also important in adult patients. Aizer and coworkers [73] recently identified that radiation therapy administered to primary brain tumors near the circle of Willis was associated with an increased risk of death secondary to cerebrovascular disease as compared to radiation to distant sites. Adults irradiated for pituitary adenomas (especially males) are also at risk for delayed stroke and TIA [74].
A recent literature review between 1978 and 2013 identified 46 patients with 69 intracranial aneurysms within the irradiated field. The mean age at radiation exposure was 34 years and the mean lag time between radiation and diagnosis was 12 years (range, 4 months to 50 years). Aneurysms were saccular in 83%, fusiform in 9, and 9% were considered pseudo-aneurysms. Just over half of the aneurysms presented with hemorrhage [75]. Aneurysms can develop after radiosurgical treatment as well as external beam radiation [76]. There is a high rate of rupture in radiation-induced aneurysms and they are associated with significant morbidity and mortality. Treatment includes surgery or endovascular treatment [77].
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