Journalof Neuro-Oncology 22: 231-234, 1994.
9 1994KluwerAcademicPublishers. Printedin the Netherlands.
Clinical Study

Neurologic complications of Merkel cell carcinoma
Susan M. Snodgrass, 1Howard Landy,2 Arnold M. Markoe 3 and Lynn Feun 4
The Department ofl Neurology, University Hospitals of Cleveland~Case Western Reserve School of Medicine,
Cleveland, OHIO, USA; 2The Departments of Neurosurgery, ~Radiation Oncology and 4Medicine, University
of Miami School of Medicine, Miami, Florida, USA

Key words: Merkel cell carcinoma, leptomeningeal carcinomatosis intrathecal chemotherapy, Ommaya reservoir
Abstract
We describe a 61-year-old man with a multiple neurologic complication of Merkel cell carcinoma, a rare skin
cancer. An enhancing brain mass, and cytologically proven leptomeningeal disease produced a succession of
symptoms including seizures, bilateral radiculopathies, myoclonus, a cauda equina syndrome and altered
mental status. Aggressive treatment prolonged his survival marginally.

Merkel cell carcinoma
Merkel cell carcinoma is a rare aggressive tumor of
neural crest origin occurring on the sun-exposed
skin of elderly people. Like small cell carcinoma
which it resembles, it is a member of the amine precursor uptake and decarboxylase (APUD) system.
This cancer, was first described in 1972 by Toker,
who referred to it as trabecular carcinoma of the
skin [1]. The cell of origin may be the Merkel cell, a
small non-dendritic cell of the basal epidermis that
functions as a cutaneous mechanoreceptor [2]. Because there are some doubts as to the cell of origin,
some authors favor the name neuroendocrine carcinoma [3].
This skin cancer arises predominantly on the
head and neck and can be difficult to distinguish
from other cutaneous neoplasms. It has a slight female predominance [3]. Excision is the primary
mode of treatment. Chemotherapy and radiotherapy are used as adjuvants in many cases because of
the tendency to invade the deep lymphatics [4]. Unfortunately, local recurrences are frequent and occur early in the disease course. The tumor can me-

tastasize to different organs including the central
nervous system [5, 6].
We report an unusual case of metastatic Merkel
cell carcinoma with clinical and MRI evidence of
both brain metastasis and leptomeningeal disease.

Case report
A 61-year-old man was in his usual state of good
health until the fall of 1990. At that time he noticed a
lump on his forehead. An excisional biopsy performed in February, 1991 was consistent with Merkel cell carcinoma. He was treated with six courses
of CAV (cyclophosphamide, Adriamycin and vincristine) chemotherapy.A year later the patient developed abnormal, paroxysmal sensations in the
thoracic region and an MRI of the thoracic spine
was negative for epidural disease. After a partial
complex seizure in December, 1991, an MRI revealed a right parietal lobe enhancing lesion, and
these dysasthesias were felt to be seizure activity.
The patient was given whole-brain radiation therapy. The seizures improved after therapy.
In March, 1992, the patient developed excruciat-

232
ing interscapular pain and numbness of the thumb
and forefinger of the right, and subsequently the
left hand. Initial MRIs of the cervical and thoracic
spine performed with and without contrast material
were negative for epidural disease. A follow-up
brain MRI was improved from the pre-treatment
scan. The numbness spread to involve more fingers,
though he noticed no leg weakness nor bowel nor
bladder symptoms. He had developed a vesicular
rash on the right face prior to his evaluation at this
institution consistent with Herpes zoster.
The general physical examination in March revealed a vesicular rash in the second division of the
trigeminal nerve distribution on the right. Otherwise the general examination was unremarkable.
The neurological examination revealed a man
whose mental status was intact. Cranial nerve examination showed a decrease in auditory acuity but
was otherwise normal. The motor examination revealed normal bulk and tone and there were no fascinations. Strength was diminished, especially in
the triceps and wrist extensors and intrinsic muscles
of the hand. There was also weakness in the iliopsoas and quadriceps in the lower extremities with
the right slightly more affected than the left. He was
able to stand on his heel and toes. Sensory testing
showed patchy changes in the upper extremities
with pinprick diminished sense in the left hand as
compared to the right. Deep tendon reflexes were
depressed in the upper extremities and increased in
the lower asymmetrically. There was an equivocal
Babinski reflex on the right. The left was downgoing. Coordination examination was unremarkable.
A lumbar puncture done that afternoon showed 24/
mm 3 WBC, protein 70 mg/dl and glucose 74 mg/dl
and cellular evidence of Merkel cell carcinoma by
cytological examination (Fig. 1). Nerve conduction
studies of the upper extremity including, motor
conduction velocity, distal motor latency and F latency of the right median nerve were normal. The
sensory conduction studies of the right ulnar and
both median nerves were also normal.
The patient was started on intrathecal chemotherapy using methotrexate (7 mg/m2), cytosine
arabinoside (40 mg) and oral leucovorin to prevent
bone marrow suppression. An Ommaya reservoir
was implanted and biweekly chemotherapy was

Fig. 1. Photographof spinalfluidcytology(H & E, 400 x magnifi-

cation).The large,irregular-shapedcellsare abnormaladherent.
They are consistentwiththe diagnosisof Merkelcellcarcinoma.
continued by the intraventricular route. The CSF
cell count and protein fluctuated and the cytology
continued to be positive throughout the patient's
course. A repeat MRI of the cervical spine, done in
April 1992, showed abnormal signal and possible
enhancement of the left dorsal subarachnoid space
at the C4-C5 level. Repeat brain MRI again
showed the right parietal mass but now showed an
enhancement surrounding the sight of the intraventricular catheter (Fig. 2). The patient developed
progressively multifocal myoclonus, headache,
ataxia and recurrent seizures. A month later he developed a cauda equina syndrome and fluctuations
in his mental status. MRI on May 19 again showed
the right parietal lobe lesion and dural enhancement. Because of these progressive symptoms, radiation therapy was begun to the cervical and lumbosacral spine for palliation. It was discontinued at the
request of the family, and the patient was returned
to a hospital closer to his home where he died several weeks later, three months after the diagnosis of
leptomeningeal carcinomatosis.

Discussion

The patient described developed widespread CNS
involvement from an infrequently occurring cutaneous tumor of neural crest origin. The overall rate
of distant metastasis from Merkel cell carcinoma
has been reported to be from 18-28% and usually

233

Fig. 2. Coronal MR image of patient demonstrating enhancing
parenchymat lesion in the right parietal lobe.

affects the liver or lungs. Regional lymph node involvement occurs in about 35%-50% [6, 7]. There
have been rare reports of brain metastases [5, 7].
One of these patients developed brain metastasis
and a presumed choroidal metastasis simultaneously with his skin lesion. These were treated with radiation therapy to the whole brain and later with an
episcleral plaque with a sustained response of 28
months at the time of the report [5]. The other patient developed brain metastasis two months after
the diagnosis of his skin tumor. He was treated with
cranial radiation therapy and combination systemic
chemotherapy and had a 10 month remission, before he died of progressive disease thirteen months
after presentation [7]. Another patient developed
hoarseness and dysphagia 17 months after the resection of the primary skin tumor. Brain MRI was
negative for parenchymal metastases, however,
there was no mention of the use of contrast with this
study. The patient was found to have cytological

and immunohistochemical evidence of Merkel cell
carcinoma, but died 6 days after diagnosis. The cerebrospinal fluid in this case showed immunoreactivity with low-molecular weight cytokeratin especially in the form of paranuclear 'buttons' or globules. It did not show reactivity with neuron-specific enolase (NSE), which is present in 20-55% of
cases of Merkel cell [6].
Cytologically, Merkel cell may be confused with
small-cell carcinoma of the lung, with both containing neurosecretory granules and both can stain positively for NSE. With disseminated disease, similar
chemotherapeutic regimens are used in its treatment [2, 4, 7, 8]. A literature review of 46 patients
showed the most commonly used drugs were doxorubicin and cyclophosphamide. Ten of 26 patients
(38%) treated in this fashion achieved a complete
response [7]. Our patient had received similar therapy. We were unable to find another case in the literature where treatment was given for the leptomeningeal disease.
Leptomeningeal carcinomatosis is an infrequent
complication of systemic cancers occurring in 5-8 %
of patients with solid tumors and usually develops
with progression of disease. It occurs most commonly with carcinoma of the breast, lung and melanoma. It is more frequent in the hematologic malignancies. The initial manifestations include headache, back pain, altered mental status, radicular
symptoms and cranial neuropathies [9]. Frequently,
the patients will have concomitant parenchymal or
epidural disease.
The diagnosis is based on the cerebrospinal fluid
(CSF) analysis. Though the initial cytology may be
positive in only 50% of the cases, the CSF is rarely
normal. Increased protein and hypoglycorrhachia
are also common findings. Neuroimaging studies
may show hydrocephalus or abnormal dural enhancement [10]. Our patient's scans demonstrated
these changes, which have not been reported previously with Merkel cell carcinoma.
Radiation therapy and chemotherapy are the
mainstays of treatment of leptomeningeal disease.
Intraventricular catheters with subcutaneous reservoirs are used to facilitate delivery of chemotherapy. The overall survival of patients with these complications is poor. Our patient survived three

234
months after the diagnosis of carcinomatous meningitis, s l i g h t l y l o n g e r t h a n t h e a v e r a g e , w h i c h m a y
b e a t t r i b u t e d to p r o m p t r e c o g n i t i o n a n d t r e a t m e n t
with local delivery of chemotherapy.

References
1. Toker C: Trabecular carcinoma of the skin. Arch Dermatol
105: 107-110, 1972
2. Knox SH, Kapp DS: Hyperthermia and radiation therapy in
the treatment of recurrent Merkel cell tumors. Cancer 62:
1479-1486, 1988
3. Weedon D: The Skin. Churchill Livingstone, New York,
1992, pp. 934-942
4. Bourne RG, O'Rourke MGE: Management of Merkel cell
tumour. N.Z.J. Surg 58: 971-974, 1988
5. Small KW, Rosenwasser GO, Alexander E, Rossitch G,
Dutton J J: Presumed choroidal metastasis of Merkel cell
carcinoma. Ann Ophthalmol 22: 187-190, 1990

6. Dudley TH, Moinuddin S: Cytologic and immunohistochemical diagnosis of neuroendocrine (Merkel cell) carcinoma in cerebrospinal fluid. AJCP 91: 714-717, 1989
7. Sharma D, Flora G, Grunberg SM: Chemotherapy of metastatic Merkel cell carcinoma: case report and review of the
literature. Am J Clin Onco114: 166-169, 1991
8. Feun LG, Saravaj N, Legha SS, Silva EG, Benjamin RS, Burgess MA: Chemotherapy for metastatic Merkel cell carcinoma. Cancer 62: 683-685, 1988
9. Grossman SA, Moynihan TJ: Neoplastic meningitis. In:
Patchell RA (ed) Neurologic clinics. Vol. 9. Neurologic
complications of systemic cancer. W.B. Saunders, Philadelphia, 1991, pp. 843-856
10. Sze G, Soletsky S, Bronen R et al.: MR imaging of the cranial
meninges with emphasis on contrast enhancement and meningeal careinomatosis. AJNR 10: 965-975, 1989
Address for offprints: S. M. Snodgrass, Department of Neurology, 11100 Euclid Avenue, Lakeside 3075, University Hospitals
of Cleveland, Cleveland, OH 44106, USA