E. David Crawford, MD, serves as Series Editor for Clinical Quandaries. Dr. Crawford is Professor of Surgery, Urology, and Radiation Oncology, and Head of the Section of Urologic Oncology at the University of Colorado School of Medicine; Chairman of the Prostate Conditions Education Council; and a member of ONCOLOGY's Editorial Board. If you have a case that you feel has particular educational value, illustrating important points in diagnosis or treatment, you may send the concept to Dr. Crawford at david.crawford@ucdenver.edu for consideration for a future installment of Clinical Quandaries.
Subacute Headache in a Patient With Metastatic Gastric Cancer
A 59-year-old man with metastatic gastric cancer presented to the oncology clinic with a 1-week history of positional headache, nausea, and vomiting. He stated that the headache was located in the frontal region, was 8 on a scale of 10 in intensity.
Figure: Cytology From the Patient’s Initial Lumbar Puncture
The Case:A 59-year-old man with metastatic gastric cancer presented to the oncology clinic with a 1-week history of positional headache, nausea, and vomiting. He stated that the headache was located in the frontal region, was 8 on a scale of 10 in intensity, and was associated with standing from a lying or sitting position. The headache and associated nausea and vomiting would subside once he returned to a supine position. He denied vision changes, vertigo, difficulty with speech, weakness, and changes in gait. He had been diagnosed with gastric cancer 11 months earlier, with an elevated alkaline phosphatase level of 1,500 U/L, and a subsequent positron emission tomography (PET) scan demonstrated widely metastatic disease throughout his skeleton. Biopsy of a right pelvic lesion revealed adenocarcinoma, and subsequent esophagogastroduodenoscopy (EGD) demonstrated poorly differentiated gastric adenocarcinoma. He was currently on his third line of therapy (with ramucirumab and paclitaxel), since his disease had progressed on two prior regimens (epirubicin, oxaliplatin, and capecitabine [EOX]; and irinotecan).
Physical examination at the time of admission revealed stable vital signs with no neurologic deficits. There was no evidence of Brudzinski or Kernig signs. Laboratory tests were only significant for a sodium level of 128 mmol/L. The patient underwent MRI of the brain and cervical spine on the day of admission; the scan showed mild prominence of the lateral ventricles and edema at the C4 vertebral body, thought to be related to degenerative disease. Magnetic resonance angiography of the cervical spine on the day of admission showed no evidence of vertebral dissection. MRI of the thoracic and lumbar spine demonstrated diffuse osseous metastatic disease, without evidence of fracture or spinal canal impingement. No leptomeningeal enhancement was seen on any MRI.
On hospital day 1, the patient was sitting up to use a urinal at the bedside when he suddenly fell back into bed, demonstrating what appeared to his nurse (who witnessed the incident) to be tonic-clonic seizure–like activity. His sodium level was found to be 117 mmol/L, and he was placed on continuous electroencephalography monitoring and transferred to the medical intensive care unit, where he received hypertonic saline followed by fluid restriction, for newly developed syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Once stable, the patient underwent an initial lumbar puncture, which demonstrated an opening pressure of 35 cm H2O, with clear, colorless fluid that had 28 white blood cells per μL (with 93% monocytes), 12 red blood cells per μL, a glucose level of 18 mg/dL, and a total protein level of 83 mg/dL. Cytology taken from the initial lumbar puncture returned with numerous vacuole-laden cells with a signet ring–like differentiation consistent with metastatic leptomeningeal carcinomatosis (Figure).
Given this diagnosis, the patient had an Ommaya reservoir placed for intrathecal chemotherapy administration, with his first dose given on hospital day 15. He tolerated this procedure well and was discharged home later that day for ongoing intrathecal chemotherapy as an outpatient.
Discussion
Leptomeningeal carcinomatosis is a result of solid tumor cell infiltration into the leptomeninges of the central nervous system. Although more common with breast and lung cancers and melanoma, it can still occur in patients with gastrointestinal tumors such as gastric adenocarcinoma, with estimated rates of 0.16% to 0.69%.[1,2] Although rare in this setting, when it does occur, leptomeningeal carcinomatosis is often found in advanced gastric cancer of signet cell pathology, as in this case.[3] Gastric adenocarcinoma leptomeningeal disease can present with various neurologic manifestations, such as headache, nausea, vomiting, altered mental status, and seizure; of these, headache is the most common presenting symptom, seen in 66% of cases.[1] These symptoms may correlate with increased intracranial pressure resulting from hydrocephalus caused by the disease process itself. In a study of nine patients with leptomeningeal disease secondary to gastric adenocarinoma, seven had elevated opening pressure on lumbar puncture, just as in this patient.[4] Additional cerebrospinal fluid (CSF) findings in patients with carcinomatous meningitis are typically elevated protein level, moderately low glucose level, and lymphocytic-predominant leukocytosis, most of which were seen in our patient. Imaging can also be helpful in the diagnosis of this disease, since leptomeningeal enhancement can be seen on both CT and MRI, although MRI is usually superior, with two times greater sensitivity and specificity. Some physicians believe it is important to perform an MRI prior to a lumbar puncture, as the procedure alone may lead to some diffuse meningeal enhancement. The rate of false negatives with an MRI is estimated to be 30%, as we appreciated in our patient.[5] For any carcinoma, a single lumbar puncture also frequently results in a false negative; this occurs in 40% to 50% of patients with pathologically proven leptomeningeal carcinomatosis, which is a justification for performing at least three lumbar punctures over several days if the initial CSF cytology is negative.[5]
The prognosis of solid tumor leptomeningeal carcinomatosis is poor, with an average overall survival of 3 months.[4] Treatment of leptomeningeal disease is limited and often requires intrathecal chemotherapy, as most of the current systemic treatments do not cross the blood-brain barrier. Standard first-line intrathecal chemotherapy continues to be with methotrexate; if the patient continues to have a good performance status, it is also reasonable to continue systemic chemotherapy.[6] Radiotherapy has also been used in bulky solid tumor disease in addition to the above therapies.[7] In patients with poor performance status, it is recommended to proceed with best supportive care.
In conclusion, although gastric adenocarcinoma is a rare cause of leptomeningeal disease, it should be high on the differential diagnosis in a patient with metastatic disease and new neurologic complaints, such as headache, nausea, and vomiting, even in the setting of normal imaging.
Outcome of This Case
Unfortunately, 2 days after his discharge (following his first dose of intrathecal methotrexate), the patient was readmitted with altered mental status and was found to have worsening hydrocephalus. After several attempts to reduce the intraventricular pressure by removing CSF through the Ommaya reservoir and placing a lumbar CSF drain, it was determined that placement of a ventriculoperitoneal (VP) shunt was required. Palliative placement of the VP shunt allowed the lumbar CSF drain to be removed, and the patient was able to be discharged from the hospital. The VP shunt was equipped with a valve programmable for near cessation of CSF flow to allow for continuation of intrathecal chemotherapy. However, the patient could not tolerate the VP shunt closure for more than 4 hours, and intrathecal chemotherapy was thus discontinued. He received palliative chemotherapy with ramucirumab and paclitaxel for 2 months, and had stable disease until his performance status worsened, at which time he was transitioned to comfort care and hospice. He died 4 months after the intial diagnosis of leptomeningeal carcinomatosis.
Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
References:
1. Kim M. Intracranial involvement by metastatic advanced gastric carcinoma. J Neurooncol. 1999;43:59-62.
2. Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer. 1982;49:759-72.
3. Noguchi Y. Blood vessel invasion in gastric carcinoma. Surgery. 1990;107:140-8.
4. Kim NH, Kim JH, Chin HM, Jun KH. Leptomeningeal carcinomatosis from gastric cancer: single institute retrospective analysis of 9 cases. Ann Surg Treat Res. 2014;86:16-21.
5. Taillibert S, Laigle-Donadey F, Chodkiewicz C, et al. Leptomeningeal metastases from solid malignancy: a review. J Neurooncol. 2005;75:85-99.
6. Grewal J, Saria MG, Kesari S. Novel approaches to treating leptomeningeal metastases. J Neurooncol. 2012;106:225-34.
7. Berg SL, Chamberlain MC. Current treatment of leptomeningeal metastases: systemic chemotherapy, intrathecal chemotherapy and symptom management. Cancer Treat Res. 2005;125:121-46.
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