CNS Melanomas:

 

Dr. A. Vincent Thamburaj,   

Neurosurgeon, Apollo Hospitals,  Chennai , India.


CNS melanotic lesions include, the rare primary melanomas, and the commoner secondary melanomatous deposits.

Occasionally other common intracranial tumors also show melanotic pigmentations.

 

 Classification:

 

Russel & Rubenstein (1989)'s informative classification is given below:

     1) Normal meningeal pigmentation - melanocytosis 

     2) Neurocutaneous syndrome (Patchy meningeal pigmentation, may be familial, no pathological sequelae) 

     3) Neurocutaneous melanomatosis (diffuse meningeal pigmentation, neural infiltration, hydrocephalus, very rarely familial).

     4) Primary meningeal melanocytoma (synonymous with melanotic meningioma, pigmented meningioma, cellular blue naevus

         biologically and histologically benign, local recurrence is common, mitosis are rare, necrosis and hemorrhage are rare,

         50% may be spinal often associated with cervical nerve roots). 

     5) Malignant meningeal melanoma (leptomeningeal tumor, may be intra-axial or extra-axial, biologically benign or

         frankly malignant, leptomeningeal seeding, may arise in any of the above settings, diffuse multi-focal nodular pattern,

         50% not associated with cutaneous nevus, 4% of these tumors may be associated with neurofibromatosis,

         nevus of Ota, Sturge Weber syndrome).

 

For practical purposes, they may be classified as primary melanomas, secondary melanomas, and melanotic tumors.

 

WHO(2000)  classifies primary melanomas as,

        1) Diffuse Melanocytosis

        2) Melanocytoma

        3) Malignant melanoma

        4) Meningeal Melanomatosis

 

 Pathology:

 

Primary CNS melanomas: 

Melanocytes originate from the ectodermal cells of the neural crest by the 6th week and migrate in their destination reaching the skin by the 10th week and the meninges by the 20th week of embryological development. These cells produce melanin pigment contained in melanosomes and are found in the epidermal-dermal junction, uveal layer of the eye and importantly in the basal meninges, piamater and on the ventral aspect of the medulla. The convexity is free.

Increased number of melanocytes in the central nervous system in association with congenital melanocytic naevi a phenomenon is known as Neurocutaneous melanosis. Thick sheets of melanocytes are found in the pia and arachnoid, most commonly over the base of the brain, and in the parenchyma of the basal ganglia, dentate nucleus, cerebellar hemispheres, pons, thalamus, and amygdala.

Neurological symptoms may occur; these may be caused by abnormalities of circulation, resorption of cerebrospinal fluid, local pressure effects, or malignant transformation.

 

Melanomas arise from melanocytes. Primary central nervous system melanoma is a rare disease in contrast to cutaneous melanoma which is the fastest increasing malignancy in western populations.  Diagnosis of a primary melanoma can be made only after a thorough autopsy to exclude a primary elsewhere. Only about 300 cases of primary cerebral and spinal melanomas have been reported. Autopsy reports suggest cerebral metastases are found in 32% of deaths from melanoma and and the incidence may be higher, if non investigated strokes are included. 

Tumors arise where melanocytes are concentrated predominantly at the base of the brain and in the upper cervical spine;

nine cases have been described in the pineal gland. Other rare sites include the pituitary gland and the choroids plexus.  It is thought that melanocytes reach these remote locations long pial arachnoid sleeves associated with blood vessels. 

 

Primary CNS malignant melanomas occur early (30-39years), when compared with cutaneous melanoma, (50-60 years).

Tumors occur either as diffuse leptomeningeal proliferations or occasionally, as a discrete mass.

Rarely, the tumor is benign (melanocytoma), but in general they are malignant from the onset.

Malignant change is complex, probably the result of polygenic deletions.

 

The presence of a giant cutaneous nevus (greater or equal to 50cm) is the only reported association. These abnormal naevi have an inherent increased risk of malignant development compared with normal naevi. The 5 year cumulative risk for neurocutaneous melanocytosis is about 2.5%.

Multiple chromosomal alterations have been identified as the cause.

Familial disease occurs in 4-10% of cases and is highly penetrant in an autosomal dominant pattern, with a likely locus on chromosome1. 

No environmental factors, unlike the cutaneous variety, have been identified.

 

Secondary CNS melanomas:

Cutaneous melanoma is a highly malignant tumor with a predilection for neural metastasis. 

Melanoma is the third most common malignancy to metastasize to the brain after lung and breast carcinoma. 

One Australian series quotes a clinical incidence of 32% for cerebral metastasis. Metastastic melanomas are more common than the primary.

Some studies identify the scalp, neck and trunk as sites with a greater predilection to cerebral metastasis. The BANS regions (Upper Back, Posterior Arms, posterolateral Neck, posterior Scalp) are often quoted as being worse prognostically. This probably reflects thicker lesions at the time of late presentation.

The brain is the initial site of metastasis in 12-20% of patients. Occasionally, patients may present with brain metastases and an unknown primary. This phenomenon may be secondary to spontaneous regression of a primary lesion or de novo melanoma within the lymph nodes, gastrointestinal tract, respiratory tract, or vagina. Approximately 10-20% of patients with an unknown primary have had a pigmented lesion removed in the past or have noted a pigmented cutaneous lesion that has involuted.

 

Leptomeningeal involvement is common.

Melanoma rarely presents as a cerebral metastasis at initial diagnosis, occurring in only 2% of cases.

Frontal and parietal lobes are affected most frequently and lesions arm commonly subcortical in location and require advanced techniques of intraoperative localization.

Multiple lesions occur twice as frequently s single deposits; 16-25% of patients have the CNS as their only site of metastasis.

 

Spinal metastases constitute1% of large series and may occur at any level.

The median interval between diagnosis of cutaneous disease ad CNS involvement is variably 29 months, to 42 months.

 

Histologically, melanomas and other melanocytic derived tumors are variable in their appearance.  They are commonly composed of spindle shaped cells with large nuclei and prominent nucleoli. Mitosis may be scant or numerous. Necrosis and mitoses are hallmarks of malignancy.  

On immunohistochemistry, S-100 is expressed by almost all melanomas, though it may be variable in its intensity.  However it is also positive for schwannomas and sarcomas.  HMB-45 is more specific for melanocytic cells but may be negative in metastatic deposits.  Thus its positivity in cerebral and spinal lesions may suggest primary disease.  Melanomas do not express epithelial markers.

 

 Clinical features:

 

Presentation is usually due to increased intracranial pressure with headache being the primary symptom in 45-50%, seizures in 15-22%, motor disturbance in 15% or a cerebral catastrophe in 24% of cases at diagnosis. 

 

 Imaging:

 

On CT scanning the  melanoma is characteristically hyperdense and enhances uniformly; areas of cystic formation are not uncommon.  Hemorrhage and necrosis are common. Lesions are usually large at the time of presentation, typically subcortical with associated surrounding edema.

 

MR scanning better demonstrates necrosis and intra-tumoral hemorrhage and edema associated with malignant. MRI may show clinically silent lesions not demonstrated on a CT scan.  On T1 images, they are hyper/isodense relative to brain. T2 signals may be variable.

Melanoma with intratumoral bleeding

CT (plain)

CT (contrast)

Lesions are solitary in 25% of cases. A solitary metastasis with hemorrhage in a young person without a known extra cerebral primary malignancy is suggestive of melanoma.

 

Melanoma is a great mimicker of other tumors. Suspicion in the presence of suspicious looking cutaneous nevus is the key.

With the advent of non-invasive imaging techniques, such as magnetic resonance imaging, it has been established that  patients with congenital melanocytic naevi may be associated with a variety of non-melanocytic anomalies of the CNS, including Dandy-Walker malformation, encephalocoele, vermian hypoplasia, arachnoid cyst, and Chiari type I malformation.  

 Management:

 

Optimal management remains elusive. CNS melanotic lesions may be asymptomatic in a small group of patients. Neither the frequency nor the natural history of asymptomatic intracranial melanosis has been established; the incidence of asymptomatic ones is considered to be low in long term follow-ups.

 

Surgery for solitary cerebral metastases is widely accepted as the best option. 

The overall outlook remains poor, average survival with conservative measures after neurological presentation is 2-3 months.   Management of multiple lesions remains problematic. 

Untreated cerebral disease progresses rapidly.  Most studies demonstrate improved survival rates with surgery.

2 year survival rate is about 10%. 

 

Leptomeningeal involvement can only be managed with adjuvant therapy. 

Adjuvant therapy includes, palliative whole brain radiotherapy in conventional doses (30 grays/18 fractions) against cerebral melanoma provides symptomatic relief in up to two thirds of patients. 

Stereotactic radio surgery may be a suitable alternative treatment for tumors of less than 3 cm diameter as well as for debilitated patients or those with deep lesions unsuitable as surgical candidates.

Stereotactic radiotherapy may be combined with whole brain palliative radiotherapy.

 

Steroids are effective in symptomatic relief but only extend survival to two months, on average.

Most chemotherapeutic drugs have been used against melanoma.  None has been shown to be superior in isolation or in combination therapy. Dacarbazine (DTIC) is the only chemotherapeutic agent approved by the US Food and Drug Administration (FDA) for melanoma. The exact mechanism of action of DTIC is unknown. The drug is administered intravenously at a dose of 2-4.5 mg/kg/day for 10 days. This may be repeated at 3-week intervals. Other useful drugs include decarbazine, nitrosureas, and vinca alkaloids which may produce partial remission in 15-30%, and complete remission in 5-10% of cases. However remission is short-lived. 

 

Melanoma has provided a useful model for immunotherapy.  Interesting results have been achieved with large doses of alpha-interferon and interleukin-2 but remission is partial and short lived.  Specific tumor infiltrating lymphocytes selected and expanded from tumor specimens and cultures with interleukin-2 demonstrate tumoricidal effect.  Immunotherapy may offer an effective means of eliminating small volumes of residual disease, and as such may be of benefit to patients having undergone resection of cerebral lesions.

 

 Prognosis:

 

Neurologically symptomatic CNS melanosis is considered to carry a very high mortality rate. Hence, it has been suggested that the children with a congenital melanocytic naevi greater than 2 cm in diameter on the head or over the spine, should have a careful neurological and developmental assessment by a pediatrician at presentation, and should continue to be followed closely during at least the first two years.

Untreated cerebral disease is rapidly fatal within 1 month of diagnosis.  Steroids may extend survival a further month. Whole brain radiotherapy improves quality of life for 2-4 months before fatal remission occurs.  Average survival after surgery is better than 9 months but few patients survive beyond 12 months.  Focused radio surgery requires further evaluation but is a good option for the patient with unresectable disease or in poor clinical condition not suitable for craniotomy.  Immune system activation and modification may provide further windows of opportunity for treatment of systemically active disease as well as for minimal volume residual disease.

 

Other melanotic CNS tumors:

 

Other neural crest derived cell lines may also produce melanin.

Accordingly, those tumors may also exhibit pigmentation that resembles that which is seen in melanocyte derived tumors; they have no clinical significance.  Medulloblastoma, ependymoma, choroids plexus papilloma, meningioma, astrocytoma, acoustic neuromas and pituitary adenoma may appear pigmented and be melanin positive. Melanotic schwannoma may be difficult to differentiate from primary nerve root differentiate from primary nerve root melanoma. Differentiation between meningeal melanomas, true melanotic meningiomas and melanotic schwannomas is even more difficult because of common reactivity to immunohistochemical markers.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


 

from Peer Reviewed Resources only

 

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