Clinical Presentation and Management of Brain Metastasis in a Sample of Iraqi Patients

Brain metastases are neoplasms that originate in tissues outside the brain and spread secondarily to involve the brain [1] This may result either from direct local extension of the primary growth, or from blood born metastases [2]. The intracranial compartment is a common site of metastatic cancer. Between 20 and 40% of patients with systemic cancer developed brain metastasis. Such metastasis can be extra axial in nature (e.g. involving the dura and subdural space, or leptomeninges and subarchnoid space), but most commonly they occur within the brain parenchyma [3]. However, the importance of intracranial metastases is not primarily due to its frequent occurrence, but to the fact that manifestations of metastases affecting the brain are usually more overt and disabling and if untreated tend to be rapidly lethal if compared to metastases to other organs such as lung and liver (in which the incidence of metastases is even higher).


Introduction
Brain metastases are neoplasms that originate in tissues outside the brain and spread secondarily to involve the brain [1] This may result either from direct local extension of the primary growth, or from blood born metastases [2]. The intracranial compartment is a common site of metastatic cancer. Between 20 and 40% of patients with systemic cancer developed brain metastasis. Such metastasis can be extra axial in nature (e.g. involving the dura and subdural space, or leptomeninges and subarchnoid space), but most commonly they occur within the brain parenchyma [3].
However, the importance of intracranial metastases is not primarily due to its frequent occurrence, but to the fact that manifestations of metastases affecting the brain are usually more overt and disabling and if untreated tend to be rapidly lethal if compared to metastases to other organs such as lung and liver (in which the incidence of metastases is even higher).
At present, the prevalence of brain metastases among cancer patients is estimated to be 20-40%. Metastatic brain tumor derived from cancer of lung are the most common type, making up 40-60% of the total, followed by those derived from breast cancers (15-20%) and melanoma (10-20%) depending whether the data come from a clinical or autopsy series. Colorectal and renal cell carcinoma account for 5-10% each. These five sources are responsible for most cerebral metastasis. Melanoma has the highest propensity to spread to brain, but is less well represented than lung cancer in large series because of the much greater incidence of lung cancer in the general population. In patients younger than 21 years of age, brain metastases arise most often from sarcomas (Ostoegenic sarcoma, Rhabdomyosarcoma, and Ewing's sarcoma) and from germ cell tumors (e.g. neuroblastoma).

Patient and Methods
This is a prospective study of (25) patients of metastatic brain tumors who were admitted to the Neurosurgical Hospital of Baghdad in the period between January 2004 and January 2007.
The patients included in this study are those who had an operation for intracranial lesion and had a histopathological proof to be a metastatic tumor, or those who had no operation to the intracranial lesion,but have a histopathological proof of primary lesion. Patients with unknown primary lesion and a clinical and radiological suspension of having an intracranial metastasis and managed depending on this suspension were excluded from the study.
The data were collected from the patient in the hospital mentioned above including the descriptive data, the neurological presentation, and the previous history of the primary lesion, the important investigations, the details of the operation and the histopathologieal report. Blood samples were obtained for all patients to test the complete blood picture (CBP) including the Hb, PCV, and ESR [4,5] Blood biochemical studies were done including random blood sugar (RBS) and blood urea for all the patients, serum creatinine for all patients, and liver function tests for all patients.

Skull X ray
In both the postero-anterior and lateral views, looking for any raised intracranial pressure (ICP) e.g. demineralization of the dorsum sellae; sign of mass effect e.g. shift of calcified pineal body to one side; or any abnormal calcifications [6,7].
The features studied include: a) Multiplicity, which means single or multiple metastases, could be found. b) Site of metastases.

c)
Tumor density (compared to the brain). d) Perifocal edema and mass effect. e) Associated hydrocephalus.
f) Presence of calcification.
MRI pictures were obtained from the records of the patients.

Management Medical
All the patients received dexamethasone 4 mg 6 hourly IV after the CT diagnosis even for those who had no operation for the intracranial lesion. Carbamazepine in a dose of 200 mg 2-4 times daily was used in 13 patients, 6 of them had seizure at time of presentation, and the other 4 were given the Carbamazepine prophylactically in the preoperative period [8,9].

Surgical
Surgery was done for 13 patients. The type of the operative intervention was determined according to the site, size of the tumor, age of the patients, and his medical and general conditions regarding fitness for surgery and anesthesia. The management of the primary lesion also played a role in the management of the intracranial metastasis. All the 13 patients were operated under the general anesthesia (GA). The surgery was burr-hole biopsy, craniotomy, or a posterior fossa craniectomy. The last two were either with total removal of the tumor (macroscopically completely removed), [10,11] or subtotal removal (significant part left because it was inaccessible or invading important structures). The cystic component of the tumor was aspirated in those tumors that are not removed totally to achieve a better decompression. The pathological specimens were preserved and send for the histopathological study to confirm the diagnosis of metastasis.

Radiotherapy
All of our patients in this study received radiotherapy for the intracranial lesion after histopathologieal diagnosis of the secondary lesion by operation in 13 patients, or by radiological diagnosis in-patients with a known primary lesion. The radiation was in the form of whole brain radiotherapy (WBRT) [12,13] in a dose ranging from 2000 -4000 rad in 2-4week.

Result Incidence
During the period of study (from Jan.2004 to Jan. 2007), the incidence of metastatic brain tumors compared to other primary brain tumors was found to be 15%.

Presenting Symptoms Headache
Was the presenting symptom in 12 patients (40%), 7 were males and 5 were females. It was of moderate severity in 7 patients and markedly severe in 5 patients [14,15]. The headache was generalized in 9 patients, occipital in 4 patients, and bifrontal in 2 patients. sided weakness in 3 cases, left-sided weakness in 2 cases, [16,17] and right-sided facial weakness in one case.

Fit
Was the presenting symptom in 2 patients (8 %), 1 was males and 1 was females. The fit was generalized in both cases.

Deterioration of consciousness
Was the presenting symptom in 2 patients (8%) were males. It was progressive.
Unsteady of gait: was the presenting symptom of 1 patient (4%) was female.
Double vision: was the presenting symptom of 1 patients (4%) was male.

Duration of the Presenting Symptoms
This is the period from the appearance of the presenting complaint to the date of the medical consultation. The range was from few hours to more than a year. The onset was regarded to be sudden if the [18,19] duration was less than 1 month, and this is seen in 12 patients (48 %) (  Figure 3).

Interval between diagnosis of primary tumor and cerebral metastasis
This is an important aspect in the management of patients with cerebral metastasis. It is the time elapsing from the detection of the primary tumor until the occurrence of neurological signs. In this study we found 15 patients (60%) with a diagnosed primary tumor. Six patients of them presented in the first 6 months after the diagnosis of the primary tumor, 4 patients presented after 6 months -years, 4 patients presented after 1-5years, and only 1 patient presented after more than 5 years (it was a transitional cell carcinoma of the bladder). This is shown in the (Table 3).  Figure 4).

Headache
The relation between number of intracranial metastases and the occurrence of headache is shown in [20,21], (Table 6), and indicates that multiplicity does not affect the occurrence of headache.  Sign: They are summarized in (Table 8 & Table 9).

CT Scan:
This was done for all the patients, 9 of them without I.V contrast, and 16 of them with I.V. contrast enhancement. Ten patients (40%) have single brain metastases, and 15 patients (60%) have multiple brain metastases Fig.(3.6) .In the 10 patients having single brain metastasis, the location [24,25] of the metastasis in relation to the brain was shown in (Table 10) and the relation of the primary origin of the tumor to multiplicity is seen in (Table   11). The density of the tumors was variable. 21 patients (84%) have solid tumors, and 4 patients (16%) have a cystic component of the tumor . The density of the solid tumors was isodense in 9 patients, hypodense in 7 patients, mixed density in 2 patients, and hyperdense in 3 patients. Visual field defect 1 4       (Table 12).

Pathological studies
The specimens taking during the operation of the 13 patients who had operations for the intracranial metastases were preserved in formalin and sent for histological studies to have paraffin sections.

Gross pathology
The tumor color was grayish-pink in 8 patients and yellowishwhite in 5patients. The texture was soft in 11 patients and firm in 2 patients. No calcification could be identified in any patient [31,32] Dural attachment of the tumor was noticed in 3 patients, 2 of them were of breast carcinoma origin and 1 patient of unknown primary.

Radiotherapy
12 patients (48%) who have a histopathological diagnosis of the primary tumor with a clinical and radiological evidence of the metastatic brain tumor were sent for radiotherapy without surgery for the intracranial lesion [35,36].

Discussion
The Incidence of metastatic brain tumor in our study was 15% of the total intracranial tumors. This is higher than the incidence in old series that suggest the incidence to be 7-10 % l,3, but still lower than the recent studies which revealed that the metastases outnumber all other intracranial tumors combined.24This incidence may be increased in the future in Iraq by the more use of modern neuroimaging techniques (such as availability of MRI) and by more careful autopsy studies on cancer patients.
The Gender distribution shows male preponderance in the incidence of metastatic brain tumors was noticed in this study (male: female ratio 1.5:1) [37,38]. This was also seen in other studies e.g. in Simionescu MD3 (male: female ratio 1.5:1). This is because of the higher frequency of metastases of pulmonary origin  [39,40].This is also seen in recent studies, which showed the age to have a correlation with the incidence of certain cancers.

Am J Biomed Sci & Res
Presenting symptoms: Headache was the presenting symptoms in 40% of cases. This is compared with 50 % in other series. 4 It is markedly sever in 50% of those patients and this could be related to the rapid growth of the metastases. Focal weakness was the presenting symptom in 28% of the cases, which was usually a localizing sign of the lesion. Most of them responded to medical treatment with steroids, which indicate that it is due to brain edema. 8% of the cases presented with fit, which was generalized in all of them, and 55.5% of those patients presented with fit have multiple brain metastases. This shows that the more the number of the intracranial lesions, the more liability of the patient to present with fit. 8% of the patients have presented with deterioration in the level of [41,42] consciousness that was progressive in 50% of them and 50 % of them have a single metastatic brain tumor and supratentorial in all of those patients. This may be compared with otherstudies e.g. Simionescu MD3, who record the mental symptoms in 18 % of patients.
The duration of the presenting symptoms was under 1 month, which is regarded to be rapidly progressing, in more than 48% of our patients in this study which is more than recorded in Simionescu MD3 study who record 18.5 % of patients presented within 1 month [42,43]. This may show the rapid and aggressive growth and behavior of the metastatic brain tumors in this study. In our study the duration of the presenting symptoms in about 76% of the patients was not more 3 months.
In discussing the interval between the diagnosis of the primary tumors and cerebral metastasis we will compare the results that IV. For the metastases of digestive system origin, the interval was up to 1 year in100% of our patients, while was the same in only 33.33 % of the patients in the other study.
In summary this interval in found to be shorter in this study of lung, GIT and longer for breast and bladder than that recorded in Simionescu3 study for all the primary origins. This may show the more aggressive behavior and metastatic tendency of all cancers in our country in the last few years.
The common primary cancer to metastasize to the brain in our study was from the lung and it accounts for 28% of the patients. Headache was present in 80% of the patients in our study that is more than recorded by other studies6,24 which was 50%.
Early morning headache was described in only 19% of the patients, which is less than the 40% recorded by the Patchell RA study.22 This may be related to the unawareness of some patients to this character. Our study showed that the incidence of occurrence of headache is the same for the patients with single or multiple brain metastases, [45,46] while Patchell RA et al study showed a higher incidence with multiple brain metastases (44%) than with single brain metastases (32%).
Vomiting was recorded in 60% of the patients and all of them have headache. It was more in patients having multiple brain metastases (66.6%) than those with single brain metastasis (33.3%). [47,48] Focal weakness was present in 48% of our patients which is comparable to other studies6 that recorded it in 40 -60% of the patients.
Seizures were recorded in 36% of our patients, which is more than other studies3'6 that recorded it in 15-25% of the patients, in our study 2/3 of these patients have multiple brain metastases, and this is also recorded in other studies.
In the past history we found that more than 60% of the patients Papilledema is a sign of raised ICP. This was present in 48%of

Am J Biomed Sci & Res
Copy@ Ihssan S Nema our patients, which is comparable to the result of the Simionescu study which was 44.6%, but is more than that recorded in other series that show papilledema to occur in 10% of the patients6 ,and [51] in study which record it to be uncommon. We find in our study that papilledema is more common with single brain metastasis, and with the tumors in the infralentorial regions, while [52,53] in his study3 showed that the number of metastases had no significant effect on the frequency of papilledema.
Motor deficit is an important localizing sign and was recorded in 40% of our patients which is comparable to other studies recording focal weakness to occur in 40-60% of their patients. 6 In those cases that motor weakness occurred progressively it was induced by progressive infiltration of the motor cortex or corticospinal tract, and in the other cases that it occurred after fits it was caused by postictal exhaustion.
Ataxia was present in 12% of our patients, which is less than that recorded in other series that record it in 20 % of the cases.1,6 All of the patients had' an involvement of the cerebellum by metastases.
Dysphasia was present in 8% of our patients, which is comparable to other studies that record it in 10% of their patients.
It was a good localizing sign in our study.
CT Scan of the brain showed that 60%of our patients have multiple brain metastases which is comparable to the 51% recorded by [54,55] study20, but is still lower than that recorded by studies that depend on the autopsies of the died cancer patients that record multiplicity in 60-85% of the patients.24 This percentage will also be higher by the more use of other sophisticated investigations such as the MRI. In comparing the distribution of the metastases in the brain of our study and [56]study we will find the following: Parietal with mild-severe surrounding edema and edema is more marked with multiple melastases, that cause a mass effect on the adjacent structures and ventricular system causing hydrocephalus in 20% of the patients [60,61].
In the medical treatment, the steroids were used for all of our patients even for those who had no surgical treatment. Their effect is not only through the reduction of perifocal edema, but also they decrease CSF production, slowing neoplastic growth and may affect neurons directly to improve their function. [62] Most of the clinical features of the patient will be resolved after the use of the steroid.
The signs, which persist after steroid therapy, denote a destructive lesion. This predicts a poor chance for improvement of the neurological deficit after surgery. The anticonvulsant medication is used either for those patients with documented fits preoperatively, or as a prophylactic drug i.e. during the perioperative period.
In the surgical treatment, 52% of our patients were treated surgically for the metastatic brain lesion, which is less than that reported by the study (88.25%). This shows that in our country the metastatic brain tumors are still regarded of poor prognosis, and most of our surgeons are not exposing such patients to surgery but they usually use other treatment modalities, which is usually radiotherapy. The surgery was done for patients with single brain metastasis (60%) more frequently than those with multiple brain metastases (46.6%). The type of surgery was a burr-hole biopsy in 10% and craniotomy in 50% of the patients with a single brain metastasis, while for the patients with multiple brain metastases the burr-hole biopsy done in 33.3% and craniotomy in 13.3%.
This in summery shows that the tumor removal by a craniotomy operation is more frequently done with single lesions because it is easier and regarded to be of better prognosis than multiple lesions.

Conclusion
Metastatic brain tumors are common in Iraq, but the incidence is still less than reported in the developed countries. It is more common in males. The ages of most of the patients lie between 40-59 years. The duration of the symptoms is less than one month in 48 % of the cases.. The interval between the diagnosis of the primary tumor and the brain metastasis is less than one year in 66.6 % of the patients with known primary, which indicates the aggressive behavior and metastatic tendency of cancers. The most common primary site is the lung, next is the breast, and the third is the bladder.
Forty percent of the patients have unknown primary tumors . Papilledema occurred in 48% of the patients and was more common with single brain metastasis and with tumors in the infratentorial region.. Metastatic brain tumors are multiple in 60% and single in 40% of the cases. 70% of the metastatic tumors are in and around the parietal lobe of the brain. Most of the metastases from lung origin are multiple (71.4%), and most of the metastases from breast origin are single (80%). Clinical improvement is seen after steroid administration in most of the patients. Radiotherapy is still the main treatment modality used for patients with metastatic brain tumors in our country either postoperatively or without surgery.
Adenocareinoma is the most common histopathological diagnosis of the brain metastases; next is the undifferentiated carcinoma and the third is sequamous cell carcinoma.