Metastatic tumors involving the central nervous system (CNS) are common and occur
in 20 to 40% of patients with a systemic malignancy.[1]
[2]
[3] The frequency of intracranial metastases has increased in the recent years due to
increased survival with better treatments of primary systemic disease and improved
radiographic imaging. Common primary sources include lung, breast, and skin malignancies,
and less frequently gastrointestinal, renal, prostate, testicular, and ovarian cancers.[1]
[2]
[4]
[5]
[6] In up to 15% of patients, the primary site of malignancy is not known.[1] Some neoplasms, such as melanoma, small-cell lung cancer, and choriocarcinoma, exhibit
a unique “neurotropism,” or propensity to spread to the CNS.[4] Among children, the most common tumors that metastasize to the brain are neuroblastoma
and sarcomatous tumors such as rhabdomyosarcoma, Ewing’s sarcoma, and osteogenic sarcoma.[3]
Metastatic involvement of the cranial base may also be seen in ~4% of patients with
systemic malignancies. In particular, malignancies of the breast, lung, and prostate
have a tendency to secondarily involve cranial base structures.[1]
[2]
[4]
[5]
[6] Most of these patients present with a cranial neuropathy. However, cranial neuropathy
in a patient with systemic cancer may also be due to meningeal carcinomatosis or at
times due to contiguous spread from a head and neck malignancy.[2]
[7]
[8] In some instances, the presentation may be confusing and mimic a cerebrovascular,
infectious, or metabolic affliction. In this unique case report, a patient developed
a jugular foramen syndrome as the initial presentation of metastatic lung cancer soon
after being diagnosed and treated surgically for extracranial atherosclerotic internal
carotid artery (ICA) disease. The pathophysiology of cranial base metastases and the
anatomical basis for the various cranial nerve syndromes that may result from this
condition are discussed.
Case Report
This 70-year-old right-handed Caucasian man with a history of hypertension, hyperlipidemia,
glaucoma, tobacco use, and a family history of lung cancer, presented to an outside
facility with 1 week of headache and 2 days of difficulty articulating words with
“speech changes.” On examination, he had mild dysarthria, a left tongue deviation
and a left Horner’s syndrome. Computed tomography (CT) of the head was unremarkable
except for age appropriate cortical atrophy. A magnetic resonance imaging (MRI) was
not obtained during the workup as the patient reportedly had severe claustrophobia.
A neurology consultation suggested that these changes were due to a left medullary
brainstem stroke and a vascular etiology for the symptoms was suspected. A carotid
ultrasound demonstrated 80 to 99% stenosis and a CT angiogram demonstrated 74% stenosis
of the right ICA. A right carotid endarterectomy (CEA) was performed without complete
resolution of his symptoms.
Three months later, he presented to the emergency department at the same outside facility
with progressively worsening headache, dysarthria, inability to eat solids or expectorate
his own oral secretions, lancinating left ear and left mastoid pain, decreased hearing,
gait instability, vertigo, vomiting, and a 20-lb weight loss. On examination, he was
noted to have left-side hearing loss, uvular deviation to the right from a paretic
left palate, a decreased left gag response, left tongue deviation, and a wide-based,
unsteady gait ([Fig. 1]). MRI of the head demonstrated a left 2.5 × 3.8 × 4.0 cm T1/T2 hypointense, heterogeneously
enhancing skull base mass involving the petrous apex, jugular bulb, cochlear aqueduct,
hypoglossal canal, and occipital condyle ([Fig. 2A, B]). The mass had eroded into and thrombosed the left transverse-sigmoid sinus junction
([Fig. 3]). At this time, the patient was transferred to our institution for tertiary care.
Figure 1 Patients showing cranial nerve XII involvement: left tongue atrophy and deviation
to the left.
Figure 2 Cranial computed tomography scan demonstrating osteolytic destruction of the left
petrous bone extending into the jugular foramen and occipital condyle.
Figure 3 Magnetic resonance venogram demonstrating complete occlusion of the left transverse-sigmoid
junction (arrow).
On arrival, in addition to the above findings, we noted a hoarse voice with a left
vocal cord paralysis along with atrophy of the left sternocleidomastoid, trapezius,
and hypoglossal muscles suggesting a chronic process. A CT of the chest, abdomen,
and pelvis demonstrated a right upper lobe pulmonary mass with mediastinal extension,
enlarged hilar lymph nodes, and multiple hepatic lesions. A CT-guided biopsy of a
hepatic lesion demonstrated nonsmall-cell lung adenocarcinoma. The patient was started
on Navelbine (vinorelbine tartrate, Pierre Fabre Pharmaceuticals, France) chemotherapy
and received 40 Gy in 10 fractions of palliative radiation therapy to the skull base
lesion. Two months later, he developed an altered mental status and on repeat imaging
was found to have watershed brain metastases. Due to his disease progression and poor
performance status, the patient and family elected to pursue hospice care. He expired
shortly thereafter.
Discussion
Intracranial metastases are the most common intracranial tumor and may be detected
at the same time as the primary malignancy in ~30% of patients.[2] At times, they may be discovered with other sites of metastatic involvement in a
metachronous fashion. In rare instances, they present in a precocious manner before
evidence of the primary malignancy.[2] Headache is the most common presenting symptom in patients with metastatic disease
to the brain. In 40% of patients, a focal neurologic deficit is the presenting sign,
while in 15 to 20%, a seizure heralds the onset of the intracranial metastatic process.
Papilledema is noted in 15 to 25% of patients and 5 to 10% of patients present with
acute stroke-like symptoms which may be due to intratumoral hemorrhage, particularly
with metastatic disease from melanoma, choriocarcinoma, or renal cell carcinoma.[7] Significant vasogenic edema surrounding a metastatic lesion is common and is often
associated with mass effect in some instances resulting in altered mental status or
impaired cognition.
Metastatic disease involving the cranial base is generally considered a late event
in the course of a systemic malignancy. However, metastatic disease is the most common
cause of jugular foramen syndrome and is often underdiagnosed.[4]
[5]
[9] Greenberg et al reported 36% of all jugular foramen lesions were metastatic in origin
with the most common primary lesions being breast, lung, kidney, and prostate cancers.[10] Streitmann and Sismanis reported that a primary was discovered 67% of the time when
a jugular foramen metastatic lesion is identified. In Greenberg’s series, ~50% of
patients had metastatic involvement elsewhere in the body before presenting with cranial
base metastatic disease.[11] Laigle-Donadey et al reviewed 279 cases of skull base metastases and noted cranial
base involvement as the first sign of cancer in 28% of patients. Prostate carcinoma
represented the primary site of malignancy in 38%; it was the most frequent cause
of skull base metastasis in men, while breast carcinoma was the most frequent cause
in women. Prostate cancer is known to metastasize to bone, particularly the vertebral
bodies, pelvic bones, femurs, and ribs.[12] Less commonly, it metastasizes to the cranial base, causing a variety of jugular
foramen or cranial nerve dysfunction syndromes. Generally, this occurs in the face
of metastatic prostate involvement of the axial skeleton, but there are rare reports
of this cranial nerve dysfunction leading to the initial diagnosis of metastatic prostate
cancer[6]; however, it is rarely an isolated occurrence and widespread metastatic disease
is usually detected in these circumstances.[6]
[9] Other neoplasms may also involve the cranial base in a metastatic fashion including
malignancies of the colon, kidneys, thyroid, lymphoma, melanoma, and neuroblastoma.
Most intracranial metastatic disease is believed to arise from hematogenous spread
from the primary tumor.[2]
[3]
[4] Circulating tumor cells travel throughout the body and interact with the local environment
at the molecular level. This results in the preferential lodging, invasion, and proliferation
of specific tumors in certain organs. This mechanism of hematogenous spread is known
as the “seed and soil” hypothesis. Embolization of tumor cells through the anterior
circulation to terminal arteries in watershed areas at the gray-white matter junction
are thought to give rise to intracranial metastatic disease. Hence, intracranial metastases
are concentrated where cerebral blood flow is greatest: 80% to the cerebral hemispheres,
15% to the cerebellum, and 5% to the brainstem. Other sites of involvement are rare.
Two exceptions to this rule include melanoma and gastrointestinal tumors. Melanoma
has a predilection to metastasize to the cerebral cortex and basal ganglia rather
than the gray-white matter junction, while gastrointestinal tumors have a predilection
to involve the cerebellum.[5]
Jugular foramen metastatic disease may not be the result of traditional hematogenous
arterial spread. Rather, retrograde dissemination through Batson’s plexus may be the
route of hematogenous dissemination in these cases.[4]
[9] Batson’s plexus is a valveless venous plexus that connects abdominal structures
with the cranial, spinal, and skull base through epidural and dural veins. This alternative
mechanism of tumor metastasis may explain the common finding of metastasis at the
thoracolumbar junction (T12-L2) and skull base via “seeding” by Batson’s plexus. T2-weighted,
T1-enhanced, fat suppression technique MRI is the best method to detect cranial base
metastases. Radionuclide and CT scans are helpful as well in detecting lytic or osteoblastic
lesions. Most metastatic lesions are lytic, but an osteoblastic mix pattern may be
seen in prostate cancer primaries. Purely osteolytic lesions might be better detected
by a study such as positron emission tomography, but in some instances single photon
emission computed tomography scans have also been reported to have positive findings.[10]
[13]
Cranial base metastases may be clinically silent but frequently present with pain
or cranial neuropathy. In fact, craniofacial pain in a patient who has systemic cancer
is a significant finding.[8] Laigle-Donadey et al identified five clinical syndromes of the cranial base secondary
to metastatic disease. They termed them orbital, parasellar, middle fossa, jugular
foramen, and occipital condyle syndromes.[12] In their review, a predominance of the parasellar and sellar syndromes (29%) was
noted while middle fossa and jugular foramen syndrome were less common being seen
in 6 and 3.5% of patients, respectively. In one-third of patients, the clinical symptomatology
did not fit into one particular syndromic classification. Patients with jugular foramen
metastases presented with hoarseness, dysphagia, and unilateral dull aching pain in
the occipital and pharyngeal regions and behind the ear. On examination, they were
noted to have involvement of CN IX through CN XII at times associated with Horner’s
syndrome.
The clinical syndromes associated with cranial base metastases in the region of the
jugular foramen are best explained by understanding the local anatomy. The anterior
surface of the jugular foramen is formed by the petrous temporal bone and posterior
surface by the occipital bone. It is anatomically divided into three compartments,
two venous and one neural.[11] The large, laterally located venous compartment houses the sigmoid sinus and jugular
bulb. The small, medially located venous compartment contains the inferior petrosal
sinus. The neural compartment is located between the two vascular compartments. It
contains the glossopharyngeal (IX), vagus (X), and accessory (XI) cranial nerves which
all originate from a descending line of rootlets in the postolivary sulcus of the
brainstem. Additional nervous structures passing within the foramen include the tympanic
branch of the glossopharyngeal nerve (Jacobson’s nerve) and the auricular branch of
the vagus nerve (Arnold’s nerve). Arterial structures passing through the foramen
include the meningeal branch of the ascending pharyngeal artery and occipital arteries.[14]
The glossopharyngeal nerve (IX) is primarily sensory with a small motor component.
It receives general visceral and special sensory input from many structures, including
the tonsils, larynx, middle ear, posterior one-third of the tongue, and carotid bodies.
It projects a small general motor efferent to the stylopharyngeus muscle, which aids
in the elevation of the larynx and pharynx. The vagus nerve (X) is diverse in function
and contributes to heart rate regulation, peristalsis, sweating, speech phonation,
and elevation of the palate. The spinal accessory nerve (XI) is a pure motor efferent
innervating the ipsilateral sternoclidomastoid and trapezius muscles.[15]
Jugular foramen syndrome, or Vernet’s syndrome, is characterized by dysfunction of
the IX, X, and XI cranial nerves.[3]
[8]
[15]
[16]
[17] Impingement of the vagus nerve at the level of the jugular foramen causes paralysis
of the laryngeal muscles resulting in hoarseness and a nasal pitch.[8]
[15]
[16]
[17] Further vagal compression results in unilateral paralysis of the soft palate and
uvular deviation to the effected side. Involvement of the glossopharyngeal nerve results
in a loss of sensation to the ipsilateral posterior tongue, decreased secretions from
the ipsilateral parotid gland, and loss of the ipsilateral gag reflex. Dysfunction
of the accessory nerve manifests as a shoulder droop, difficulty abducting the ipsilateral
arm, and rotating the head contralaterally. Further, obstruction of the traversing
sigmoid, jugular or inferior petrosal sinuses can result in intracranial venous congestion,
cerebral edema, and intracranial hypertension which may manifest clinically as headache
and papilledema.[7]
[18] Clinical variations of the jugular foramen syndrome exist. Jackson’s syndrome implies
dysfunction of X, XI, and XII cranial nerves. Collet–Sicard syndrome consists of dysfunction
of the lowest four cranial nerves (IX, X, XI, and XII), and when associated with an
ipsilateral Horner’s syndrome, it is known as Villaret’s syndrome. Tapa’s syndrome
consists of X and XII nerves dysfunction.[3]
[15] Although eponym heavy, this categorization scheme’s ultimate purpose is to aid localization
of skull base lesions.
Management of cranial base metastatic disease is complex and needs to be carefully
individualized. Surgical resection may risk worsening cranial nerve deficits or cerebrovascular
morbidity. Other complications include the risk of cerebrospinal fluid leakage or
meningitis. Conformal fractionated radiation therapy to the region of involvement
and control of the systemic malignancy with chemotherapy are frequently the best options.
Radiation therapy provides relief of pain in up to 90% of patients and may also improve
cranial nerve dysfunction with a salutary functional impact. Patients who present
with symptoms of less than 1 month duration tend to do better following treatment
with radiation therapy. The classic schedule of 30 Gy in 10 fractions is generally
employed. Patients who have lymphoma and breast cancer might have a better response
than patients who have prostate or lung cancer. In some instances, chemotherapy or
hormonal therapy is employed in conjunction with radiation therapy that might have
a positive impact on survival. Radiosurgery has been recently employed in the treatment
of recalcitrant disease following primary radiation therapy. Complications with radiosurgery
include worsening cranial nerve palsies, cerebral edema, or cerebrospinal fluid leakage.
Status of the primary malignancy and the extent of systemic metastases determine mortality
in these patients.[19]
In our report, we discuss a patient whose only initial presentation of metastatic
lung cancer was most akin to Tapa’s syndrome (cranial nerves X and XII palsy with
Horner’s syndrome), and later progressed to a Collet-Sicard syndrome with the additional
involvement of cranial nerves IX and XI. The patient initially underwent a right CEA
out of suspicion for carotid occlusion syndrome; however, his symptoms progressed
as his skull base lesion expanded. The chronicity of his symptoms, and in particular,
the atrophy of the involved muscles suggests a process that may have predated his
carotid ischemic symptoms. This delay in diagnosis obviated treatment options including
medical and radiation therapy that may have palliated the patient’s symptoms and prolonged
his survival.
