Cancer is an important and common cause of IH. Clinical and autopsy studies have found that brain tumors represent 0.9% to 11% of spontaneous IH.2,7,11,16–22
The largest autopsy study of IH in patients with cancer was performed at MSKCC from 1970 to 1981 and identified 244 patients, 57% of whom were symptomatic.1
Coagulopathy occurred in 57% of those with ICH, and 89% of these patients had hematologic malignancies, particularly leukemia (78%). ITH occurred in 38% of patients and was the second most common cause of ICH; all but 2 of these patients had a solid tumor, with melanoma and germ cell tumors being the most frequent. Hypertension was responsible for only 8% of parenchymal hemorrhages in this cohort.
Our report represents the largest clinical series of IH in patients with cancer. Systemic solid tumors were the most common underlying cancer, which differs from many previous studies where primary brain tumors accounted for the majority of malignancies.13,21,23,24
In one series of 110 patients with bleeding cerebral neoplasms, 77% had primary brain tumors and 23% had metastatic solid tumors.21
Similarly, 62% of patients with ITH in a different cohort of 58 cases had primary brain tumors.13
This changing demographic may represent longer survival of patients with solid tumors or the higher likelihood of primary brain tumors with IH to be clinically silent and thus not lead to acute neuroimaging.
The frequency of hemorrhage into intracranial neoplasms ranges from 1.3% to 14.6% and varies markedly depending on the pathology of the underlying cancer.4,7,11,12,19,21,25–27
Malignant and hypervascular neoplasms have the highest predilection for hemorrhage.12,25,26,28,29
Factors favoring hemorrhage include overexpression of vascular endothelial growth factor and matrix metalloproteinases, imbalances in the fibrinolytic cascade, retiform type capillaries, rapid tumor growth, vascular invasion, tumor necrosis, and neovascularization.30–33
Melanoma, lung, glioma, breast, and leukemia were the most common tumor types in our cohort. The high rates of hemorrhage in patients with breast and prostate cancer were unexpected. Alternatively, we saw low rates of hemorrhage in patients with renal, germ cell, thyroid, and hepatocellular carcinomas previously thought to be highly associated with ITH.
ITH, coagulopathy, or the combination of the 2 accounted for the majority of IH. Hypertension, amyloid angiopathy, and other common causes of IH in the general population were rare, highlighting the unique pathophysiology of IH in patients with cancer. Patients with solid or primary brain tumors most often bled from ITH, whereas patients with hematopoietic tumors most often bled from coagulopathy. Patients with hematologic malignancies were also most likely to bleed from the rarer etiologies in our cohort, such as trauma or hemorrhagic conversion of stroke. Previous studies had found hyperleukocytosis and DIC to be common causes of IH in acute leukemia,1,3,34,35
but both syndromes were rare in our series, reflecting the advances in therapy and changing natural history of acute leukemia.
Anticoagulation of patients with primary or metastatic brain tumors and thromboembolism is often avoided for fear of catastrophic IH despite existing data suggesting that the risk is small.36,37
One retrospective study of 42 patients with cerebral metastases on therapeutic anticoagulation found only 3 symptomatic IHs, 2 of which occurred in the setting of supratherapeutic values.36
Nineteen percent of our patients were on therapeutic anticoagulation at the time of hemorrhage, and only 3% were supratherapeutic. There was no significant association between anticoagulation and mortality, supporting the safety of this treatment in hypercoagulable cancer patients. This holds true for patients with primary or metastatic brain tumors, because nearly half of our patients had known brain lesions before IH. Furthermore, antiangiogenic therapies were not associated with a substantial risk of ITH. This was also observed in a recent study of 21 patients with glioma receiving concurrent bevacizumab and anticoagulation, none of whom developed severe IH.37
Patients with cancer have a poor overall prognosis after IH. Median survival was 3 months, and only 22% of patients lived 1 year. Despite short survival, many patients had excellent functional outcomes, and nearly half were completely or partially independent at the time of discharge. Half of our cohort was also discharged home. Mortality at 30 days (31%) was similar to that of ICH in the general population and only began to worsen compared with historic controls as time from hemorrhage advanced.38,39
This trend suggests that many patients died from their systemic malignancy and not from the hemorrhage itself. Patients with primary brain tumors had the best prognosis, with a median survival of 5.9 months. These patients lived a median of 12.3 months from diagnosis, comparable to the typical life span of patients with malignant brain tumors. Patients with hematopoietic tumors had the worst prognosis, with more than a third dying during hospitalization. This can be attributed to their high rate of coagulopathy, which in isolation was associated with a median survival of only 0.3 months. These patients typically had severe coagulopathy and would develop refractory hemorrhage into multiple cerebral compartments.
Poor prognostic indicators were impaired consciousness, hemiparesis, multiple hemorrhagic foci, hydrocephalus, and treatment for increased ICP (). Recent chemotherapy, not having a primary brain tumor, and lack of ventriculostomy also predicted poor outcome. Recent chemotherapy likely indicates patients with more aggressive disease and higher rates of pancytopenia. Not receiving a ventriculostomy may identify patients treated less aggressively. Steroid administration was common in our IH cohort (75%) and correlated with the rate of ITH (61%). Glucocorticoids were used to suppress tumor-associated edema and promote oncolysis in some hematologic malignancies; its use did not affect outcome (30-day mortality odds ratio 0.8, p = 0.45).
There are several limitations to our study, most importantly its retrospective nature. We did not address isolated subdural or epidural hematomas. Subdural hemorrhage in patients with cancer is often associated with bone and dural metastases and has a different course and outcome from IHs.40
Epidural hematomas were not included as most are postoperative at our institution. Our study also excluded outpatient hemorrhages because we had no comprehensive method of ascertainment. Hemorrhages recognized in outpatients are more likely to be asymptomatic or mildly symptomatic and unlikely to affect morbidity or mortality. Our median survival would probably improve if these hemorrhages were included. Last, MSKCC is not a designated stroke center. Some patients were likely taken to nearby stroke centers, potentially decreasing the number of larger and more disabling hemorrhages.
This study describes the unique pathophysiology and outcome of patients with cancer and IH. ITH and coagulopathy cause most IHs in patients with cancer, whereas hypertension and other causes typical in the general community are rare. Changes in etiology of IH in patients with cancer parallel improvements in management of the underlying neoplasm, particularly in the hematologic malignancies. Prognosis is generally poor, although many patients retain independence after IH and ultimately succumb to their underlying malignancy and not the hemorrhage itself.