Journal of Neuro-Oncology 63: 313–316, 2003. © 2003 Kluwer Academic Publishers. Printed in the Netherlands.

Clinical Study

Nervous system involvement by pancreatic cancer Kyung-Seok Park1 , Manho Kim2 , Seong-Ho Park3 and Kwang-Woo Lee2 Department of Neurology, Inje University Seoul Paik Hospital; 2 Seoul National University Hospital, Seoul; 3 Seoul National University Bundang Hospital, Seongnam, South Korea

1

Key words: cerebral metastasis, pancreatic cancer, spinal metastasis Summary From 1,229 consecutive patients with pancreatic cancer, seven patients who developed nervous system metastasis were evaluated retrospectively. Nervous system metastasis frequently antedated the diagnosis of the primary cancer (five out of seven patients). Four patients had cerebral metastasis. Brain computed tomography or magnetic resonance imaging revealed single or multiple cyst-like lesions with ring enhancement in half of these patients. Three patients had spinal metastasis which caused myelopathy in two. The metastatic lesions were localized to the thoracic level. Radiation therapy directed to the metastatic sites could not change the clinical course.

Introduction Pancreatic cancer (PC) is a relentlessly progressive and fatal disease. The incidence has increased significantly as the average life span of the population has lengthened. Although the prognosis is poor, recent advances in treatment with chemotherapy or chemoradiation therapy have increased the survival time for these patients. Therefore, identification of metastasis becomes more important in treatment plan. To date, few study has evaluated a large group of PC patients for the investigation of nervous system metastasis. Literature on nervous system involvement from PC has appeared only in the form of case reports [1–6] and the incidence is believed to be very rare. As a result, the clinical manifestations of nervous system metastasis from PC remain poorly described. The PC is the tenth leading primary carcinoma in South Korea [7]. The present study evaluated the clinical presentations, radiological findings, and treatment outcome of the PC patients with nervous system metastasis.

was based on computed tomography (CT), ultrasonography, and endoscopic retrograde cholangiopancreatography (ERCP) with other supportive clinical features and laboratory findings. Most of the diagnosis was histologically proven. Among this group, seven patients had clinical presentations of nervous system involvement. We analyzed their demographics, clinical manifestations, radiological findings, treatment, and outcome. Results Demography In our study, only seven of 1229 PC patients (0.57%) developed clinically evident nervous system metastasis. All patients were men with a mean age of 48.3 ± 10.1 years (mean ± SD, ranged from 29 to 62). Presentations consisted of four cerebral and three spinal metastases. The mean age was 53.3 ± 6.1 years in the cerebral group and 41.7±11.7 years in the spinal group. The cell types for PC were adenocarcinomas. The clinical and radiological findings are summarized in Table 1.

Methods Cerebral metastasis We reviewed the medical records of 1,229 consecutive PC patients seen between 1980 and 2000 at Seoul National University Hospital. The diagnosis

In two patients (patients 1 and 3), cerebral metastasis was found during the follow-up of PC. At the time

314 Table 1. Clinical features of the patients with nervous system metastasis

CM 1 2

48 51

M M

3 4

52 62

SM 5 6 7

44 52 29

Location

Other organ metastasis

Interval

Small, multiple areas Lt frontal

Lung Lung, liver, bone

4 ∗

M M

Headache, dysarthria, Rt hemiparesis Personality change, headache, aphasia, Rt hemiparesis, Rt paresthesia Behavioral change, Rt hemiparesis,aphasia Rt hemiparesis, Rt paresthesia

Lt parietal Lt frontal, Lt basal ganglia

Liver Lung

5 ∗

M M M

Back pain Myelopathy Myelopathy

T12 spine T10 spine T5 spine

Liver Liver, lung, lymph node —

∗ ∗ ∗

CM, cerebral metastasis; SM, spinal metastasis; T, thoracic; —, absent. Interval: time interval (month) between the diagnosis of PC and nervous system metastasis. ∗ Metastasis as their first manifestation.

of diagnosis, there was evidence of regional metastasis in the lung (patient 1) or liver (patient 3). During the follow-up visits, these patients presented with headache, behavioral change, hemiparesis, hemisensory deficit, or aphasia. Brain CT scan revealed single or multiple enhancing mass lesions with surrounding edema. They received treatments such as palliative cholecystojejunostomy (patient 3) and chemotherapy with FAM (5-fluorouracil, doxorubicin, mitomycin C) or 5-fluorouracil (patients 1 and 3, respectively). The mean interval between the diagnosis of primary cancer and cerebral metastasis was 4.5 ± 0.7 months (mean ± SD). After the diagnosis of cerebral metastasis, these patients received whole brain radiation therapy, which did not change the clinical course, however. In the remaining two patients (patients 2 and 4), neurological symptoms were the first manifestation of PC. These two patients presented with headache, personality change, hemiparesis, hemisensory deficit, or aphasia. Brain CT or magnetic resonance imaging (MRI) revealed single or multiple cyst-like lesions with ring enhancement in frontal lobe or basal ganglia (Figure 1). These patients already had lung metastasis detected simultaneously with development of neurological symptoms and signs. They did not receive any treatment. All patients deteriorated and died soon thereafter. The median survival of these patients after the diagnosis of cerebral metastasis was 2.9 ± 1.0 months (mean ± SD, ranged from 1.5 to 3.8). They died of progressive cachexia, hepatic failure, or sepsis.

Figure 1. T1-weighted axial MRI with gadolinium in patient 4 shows a cyst-like lesion with ring enhancement in the left basal ganglia.

Spinal metastasis All the patients presented with spinal metastasis as their first manifestation. Patients 5 and 6 already had other organ (liver, lung, or lymph nodes) involvement found simultaneously with spinal metastasis. Back pain

315 was a initial symptom in all patients. Two patients (patients 6 and 7) had radicular symptoms, which progressed to myelopathy. These patients had subsequent paraparesis, sensory deficit below a sensory level, and sphincter dysfunction. In all patients, the metastatic lesions were located at the thoracic level. Two patients (patients 5 and 6) had bone metastasis in lower thoracic spines, which caused pathologic fracture in patient 5. The CT scan showed an enhancing epidural mass compressing spinal cord in patient 7. Only one patient (patient 6) received radiation therapy, which, however, did not change his clinical course. Patients 5 and 7 refused any treatment. The median survival of these patients after the diagnosis of spinal metastasis was 4.1 ± 1.8 months (mean ± SD, ranged from 2.5 to 6). They died of progressive cachexia or sepsis.

Discussion Although PC develops in about 27,000 Americans (2% of all cancer diagnoses) each year [8,9], report on nervous system metastasis is scanty. Our study confirms that nervous system metastasis is rare (0.57%). The low incidence rates are most likely the result that patients with PC do not survive long enough for tumor cells to reach the nervous system. With all current chemotherapy regimens, patients with metastatic PC have a median survival of 3.9–7.4 months [10,11]. However, the actual incidence will be higher because the patients with advanced PC may not be evaluated adequately during the period of survival. In previous autopsy studies [12,13], the incidence rates of intracranial metastasis were higher (5.8% and 7.9%) than those in our study. The incidence of nervous system metastasis will likely increase with the improvement in neuroimaging techniques and prolongation of survival due to recent progress in treatment. Five out of seven patients in our study presented with nervous system metastasis as their first manifestation of PC. This is probably because the initial symptoms of PC itself are often non-specific and the diagnosis is usually made after the disease has spread. The tendency was prominent especially in the patients with spinal metastasis. The clinical manifestations of spinal metastasis antedated the diagnosis of the primary cancer in all three patients. This finding may be explained by the anatomic proximity between the pancreas and spines. Three out of four patients with cerebral metastasis had lung involvement simultaneously. On the other

hand, only one of three patients with spinal metastasis had lung involvement. Furthermore, all the three patients already had spinal metastasis at the time of diagnosis of the primary cancer, and the metastatic lesions were localized to the thoracic level. These findings suggest that the metastatic pathway should be different in cerebral and spinal metastases. Our result supports the hypothesis that cerebral metastasis may occur hematogenously through the lung and spinal metastasis may be mediated by local spread through venous plexus or lymphatics [14]. The usual form of intracranial metastasis was parenchymal lesion in our study. There was no leptomeningeal seeding. Brain CT or MRI showed single or multiple cyst-like lesions with ring enhancement in half of the patients with cerebral metastasis. If the metastatic lesion is centrally necrotic, then it can have a ring-like shape. It was reported that brain metastases from lung [15], prostate [16,17], breast [18], and ovary [19,20] might present as cystic lesions. Kuratsu et al. [4] reported a cystic, ring-like enhancing lesion on CT scan in one of the two patients with brain metastasis from PC. PC was also proven histologically as a primary cancer in cystic lesions of brain metastasis [21]. Therefore, metastatic PC should be included in the differential diagnosis of cerebral cystic metastasis along with lung, prostate, breast, and ovary cancers. In our study, the median survival was 2.9 months in the patients with cerebral metastasis and 4.1 months in the patients with spinal metastasis, which was not significantly different from the reported data of patients with metastatic PC [22]. Radiation therapy applied directly to the metastatic sites was not effective. None of the patients showed improvement and all died within a few months. The causes of death usually were not related to nervous system metastasis.

Acknowledgement This work was supported by Korea Research Foundation Grant (KRF-2002-003-E00135).

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Address for offprints: Manho Kim, Department of Neurology, Seoul National University Hospital, 28 Yongon-Dong, Chongno-Gu, Seoul 110-744, South Korea; Tel.: +82-2-7602193; Fax: +82-2-744-1785; E-mail: [email protected]