Secondary CNS Melanomas

Updated: Jan 24, 2019
  • Author: Alan Schaffert, MD; Chief Editor: Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS  more...
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Melanoma is a malignancy of melanocytes, which are pigment-producing cells derived from the neural crest. This condition constitutes 3% of all cancers diagnosed in the United States; it is the most lethal form of skin cancer and the third most common malignancy that causes central nervous system (CNS) metastases, after lung and breast cancer. [1] The primary tumor may occur at any location on the skin or, less commonly, on the mucus membranes or other locations. [2]

See The Case of the Middle-Aged Woman with Sudden Unilateral Vision Loss, a Critical Images slideshow, to help identify and treat malignant intraocular tumors.

The prevalence of CNS metastases in patients with a primary melanoma ranges from 10% to 40% in clinical series. Brain metastases are present in up to two thirds of patients with disseminated malignant melanoma, and metastases to the meninges occur in approximately 30% of patients with metastatic melanoma. [3] In one large series, the male-to-female ratio of cerebral metastases was 1.9:1. [4]

The incidence of melanoma is increasing faster than that of any other malignant neoplasm, except for lung cancer in women. This cancer is 10 times more common in fair-skinned white individuals than in dark-skinned individuals. For someone born in the United States in 2000, the projected lifetime risk of developing melanoma is 1 in 75. Although early recognition and surgical excision of a cutaneous primary can be curative, treatment options for metastatic disease are limited and the prognosis becomes guarded.

Primary intracranial melanoma can arise from the leptomeninges or dura mater. Primary ocular melanoma is well recognized; however, orbital involvement is usually secondary to local invasion from an ocular, sinus, or CNS source or from hematogenous spread from a cutaneous or visceral site. Neurocutaneous melanosis is a congenital disorder in which infants with giant hairy melanocytic nevi have associated leptomeningeal melanocytosis involving the brain and/or spinal cord. This leptomeningeal invasion can cause severe neurologic compromise or death. [5, 6]

Secondary CNS melanoma most often results from hematogenous spread from a known or unknown primary tumor. Metastases are typically in the parenchyma or leptomeninges. This article focuses on secondary CNS melanoma. [7]

For more information, see the following:



The 4 major histologic types of primary cutaneous melanoma are superficial spreading, nodular, acral lentiginous, and lentigo maligna melanoma. These tumors differ in their histologic and, possibly, biologic characteristics. Metastases reach the central nervous system (CNS) via hematogenous spread of tumor cells. Tumor cells are released into the circulation, arrest in end arteries, penetrate the blood-brain barrier, enter the CNS, and establish growth in the new tissue. Neurotrophins can facilitate invasion by upregulating enzymes such as heparanase (HPSE), which destroy the extracellular matrix and basement membrane of the blood-brain barrier. Although initial metastatic foci involve the gray-white matter junction, any part of the brain can be involved, including the pituitary gland, cerebellum, and cerebral hemispheres. The tumors most often are multifocal and have a unique tendency to hemorrhage.

Other common sites of melanoma metastases are skin, subcutaneous tissue, spleen, liver, lymph nodes, lungs, gastrointestinal tract, and bone.


Clinical Assessment

Individuals at highest risk for melanoma include the following:

  • Individuals with fair skin, blue eyes, freckles, and red or blond hair

  • People who tan poorly, burn easily, and have a history of blistering sunburn in the past

  • People with a history of nonmelanoma skin cancer

  • People with numerous melanocytic nevi

  • People with atypical nevi

  • Individuals with a family history of melanoma or atypical nevi

Elicit a history of previous melanoma, including the following details:

  • Date of diagnosis

  • Location of melanoma on body

  • Method of treatment (eg, type of excision, margin taken, whether reexcision was recommended and done)

  • Details from the pathology report (eg, gross appearance, excisional margin, histologic type, depth of tumor, growth phase, presence of ulceration, involvement of blood vessels or lymphatics)

  • Stage of previous melanoma

Ask patient about new or changing skin lesions. Such questions may include the following:

  • Does the patient have concerns about any skin lesions?

  • Has the patient ever had any suspicious moles removed?

  • Have any moles undergone changes in their shape, size, color, texture, and sensitivity (itching or burning)?

  • Has the patient had any bleeding or ulceration from any skin lesions?

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.

Question all patients about symptoms suggestive of central nervous system (CNS) metastases, as follows:

  • Headache

  • Nausea and vomiting

  • Visual changes

  • Seizures

  • Confusion or personality change

  • Cranial nerve palsies

  • Polyradiculopathies, especially in cases of meningeal involvement [8]

Cutaneous and reticuloendothelial examination

Document the patient’s skin phototype (SPT) (ie, Fitzpatrick skin type) and the presence of actinic skin damage. Carefully examine entire cutaneous surface, including the scalp, mucous membranes, and perianal and genital regions. Identify any pigmented skin lesions that are asymmetric, have an irregular border, contain 2 or more colors, or are friable, bleeding, ulcerated, or polypoid.

If the patient has had previous surgery for melanoma, check the primary surgical site for evidence of subcutaneous nodules indicating local recurrence or in-transit disease. Check for cutaneous nodules near or distant to the primary site.

In addition, examine the patient for lymphadenopathy, particularly draining lymph nodes at the primary site, and for the presence of hepatosplenomegaly.

Neurologic examination

The neurologic assessment includes the following:

  • Mental status examination, level of consciousness, speech abnormalities

  • Abnormalities, including funduscopy for papilledema

  • Upper motor neuron signs, hyperreflexia, Babinski sign

  • Cerebellar ataxia, gait instability

  • Sensory abnormalities

Perform careful breast, rectal, renal, thyroid, and respiratory examination to search for other possible tumors in the differential diagnosis of CNS metastases.


Differential Diagnosis

The following conditions are considered in the differential diagnosis of central nervous system (CNS) melanoma:

Other conditions that should be considered when evaluating suspected CNS melanoma include the following:

  • Arteriovenous malformations

  • Complex partial seizures

  • Dissection syndromes

  • Fibromuscular dysplasia

  • Frontal lobe epilepsy

  • Intracranial epidural abscess

  • Intracranial hemorrhage

  • Lacunar syndromes

  • Simple partial seizures

  • Subarachnoid hemorrhage

  • Tonic-clonic seizures


Diagnostic Studies

Specific blood tests for intracerebral metastatic melanoma do not exist. However, laboratory tests are based on the differential diagnosis to help rule out certain diagnoses. Different presenting symptoms, such as acute confusion versus fever and meningismus, guide the differential diagnosis and subsequent serum investigations.

Blood tests can help identify sequelae of brain metastases, such as hyponatremia in inappropriate antidiuretic hormone secretion (SIADH) or hypernatremia in diabetes insipidus. An isolated high level of lactic dehydrogenase can be presumptive evidence of metastatic disease. Serum lactate dehydrogenase levels are now part of the American Joint Committee on Cancer staging system for patients with metastatic melanoma.

Central nervous system (CNS) metastases are characterized by solitary or multiple brain lesions of different sizes and locations. About 75% of patients have multiple lesions. [4] Significant surrounding edema is usually present.

Patients with suspected brain metastases should not only undergo imaging studies of the central nervous system (CNS) but also imaging of other systems to determine whether other organ involvement exists, as this will influence management.


Nuclear Imaging

Whole-body positron emission tomography (PET) scanning is a highly sensitive and specific modality in the detection of melanoma metastases and in identifying recurrent disease. [9, 10] PET scanning detects malignant tumors based on increased glucose metabolism seen in malignant cells compared with normal surrounding tissue. F-18 fluorodeoxy-D-glucose (FDG), the radioisotope used, is a glucose analogue. FDG is taken up by normal and cancerous tissue and becomes phosphorylated and trapped within cells. Because cancer cells have markedly increased glucose metabolism compared with baseline tissue, the increased FDG uptake is easily identified.

PET scanning more accurately identifies melanoma metastases than computed tomography (CT) scanning, magnetic resonance imaging (MRI), ultrasonography, or physical examination in most tissues, except the brain and lungs. [11] Unfortunately, PET scanning is of limited use in localizing central nervous system (CNS) metastases because of the extensive baseline glucose metabolism of the brain.

Radionuclide bone scanning is indicated for suspected bony metastases.


Magnetic Resonance Imaging

Contrast-enhanced magnetic resonance imaging (MRI) is the most sensitive imaging method to document CNS metastases and meningeal involvement. This modality is preferred over contrast-enhanced computed tomography (CT) scanning, which can demonstrate features of metastatic disease, although small metastases and leptomeningeal spread may be missed.

MRI features of melanoma can be identical to those of certain other metastatic tumors because of the propensity of all these tumors to hemorrhage. The neoplasms most characterized by hemorrhage into CNS metastases can be remembered by the mnemonic “MATCH”: melanoma, anaplastic lung carcinoma, thyroid carcinoma, choriocarcinoma, and hypernephroma.

Most CNS metastases classically appear as multiple areas of hypointensity on T1-weighted MRI and heterogeneous hyperintensity on T2-weighted MRI. In addition, melanoma can be hyperintense on T1-weighted MRI and hypointense on T2-weighted MRI because of the melanin content of the tumor. However, the presence of hemorrhage may alter the MRI signal intensity and further complicate the radiologic diagnosis.

Contrast administration reveals ring, homogeneous, or nodular enhancement of the tumors; leptomeningeal or dural enhancement occurs if the tumor has invaded these sites.


Computed Tomography Scanning

As mentioned in the magnetic resonance imaging (MRI) section, enhanced computed tomography (CT) scanning can demonstrate features of central nervous system (CNS) metastatic disease, but this imaging technique may miss small metastases and leptomeningeal spread.

In general, enhanced CT scanning demonstrates solid enhancement with smaller tumors; in large tumors, ringlike enhancement is seen. With nonenhanced CT scanning, most metastases are isodense with surrounding brain tissue and may be missed. Perilesional edema may be the only finding.

Chest and abdominal CT scans may further delineate any pulmonary disease and identify intra-abdominal metastases.



Chest radiographs may reveal hilar adenopathy, single or multiple metastatic nodules, or pleural effusions.

Contrast bowel studies may reveal bowel metastases; this may be indicated in patients with anemia or blood in the stool.


Lumbar Puncture

A lumbar puncture and cerebrospinal fluid (CSF) analysis can be helpful for the evaluation of suspected carcinomatous meningitis. However, approximately 40% of patients with meningeal involvement have a normal CSF profile. [3]



Stereotactic brain biopsy by a neurosurgeon is usually not necessary if the patient has a known primary tumor and if the imaging evaluation is compatible with melanoma.

Parenchymal metastases are well-circumscribed nodules of various sizes that may be solid or partially cystic. They are surrounded by marked edema and may be filled with hemorrhage or necrotic debris.

Certain histopathologic findings in the cutaneous primary lesions are important markers for metastatic spread. Tumor thickness and the presence of tumor ulceration are the single most important prognostic factors. [12] (See Prognosis and Prognostic Factors.)

If tumor tissue is available, histologic identification of the brain lesion can be challenging, because the tumor may be poorly differentiated. In this case, special melanin stains, such as S100, Melan-A, or homatropine methylbromide (HMB) 45, can be helpful.


Management Overview

Melanoma that metastasizes to the central nervous system (CNS) is incurable. Treatment is aimed at tumor debulking, symptom relief, and palliation. Palliative care should include attention to pain, emotional and spiritual support, and nonsurgical treatment of symptoms of increased intracranial pressure (ie, steroids). The use of steroids provides symptom relief by decreasing cerebral edema.

The patient can usually be monitored on an outpatient basis. Inpatient care may be required for patients who require evaluation, surgery, or palliative radiotherapy.

Treatment options are based on the number and size of CNS lesions and the presence of extracranial disease. Several comprehensive reviews of the treatment of CNS melanoma metastases are available. [13, 14, 15, 16, 17] A brief summary of these literature reviews follows.

A multidisciplinary team consisting of a neurologist, neurosurgeon, medical oncologist, dermatologist, and radiation oncologist should manage complex cases of metastatic melanoma.


Surgical Intervention

Surgery is recommended for solitary brain metastases. The patient should have controllable systemic disease to be considered for surgery. However, surgical resection is still a viable option for symptomatic patients with one or more systemic metastases.

Surgery can significantly improve neurologic signs and symptoms; however, a proportion of patients undergoing brain surgery for melanoma can have postoperative worsening of their neurologic symptoms.

Limitations of surgery include the inaccessibility of deep-seated or multifocal central nervous system (CNS) lesions. Some patients may be too ill to tolerate brain surgery.

The effect of surgery on median survival is controversial. Long-term survival has been described in patients who have had surgical resection of a single metastatic tumor.


Whole Brain Radiation Therapy

Radiotherapy is effective for palliation. Improvement in neurologic deficits following whole brain radiation therapy (WBRT) is well documented.

WBRT can be used for solitary and multiple brain metastases [18] . However, no increase in overall survival is seen if WBRT is used alone.

Addition of postoperative WBRT is considered by some to be more effective than surgery alone in local tumor control, as microscopic foci are likely to exist even after complete tumor resection. When WBRT is used in combination with tumor resection, increased overall survival may be seen.


Stereotactic Radiosurgery

Stereotactic radiosurgery (SRS) [19] involves high doses of radiation delivered to the tumor in one fraction, in a single session, with relative sparing of surrounding tissues. This treatment is used for single or multiple central nervous system (CNS) metastases; patients with single lesions have a better outcome. [20]

Local tumor control rates with SRS are quoted as 76-97% in the literature. Median survival with SRS ranges from 4 to 7 months.

One of the main advantages of SRS is the treatment of surgically inaccessible metastases. SRS (with or without whole brain radiation therapy [WBRT]) can provide effective local control comparable to surgery plus WBRT.

Rare side effects of SRS include CNS radiation necrosis that requires surgery or systemic steroids. This complication may be seen in 5-10% of patients receiving SRS.



Secondary central nervous system (CNS) melanoma is uniformly fatal. Death usually results because of increased intracranial pressure or destruction of vital brain tissue. The deterioration can be insidious or acute.

Focal neurologic signs are very common and may lead to significant morbidity [21] . In addition, patients may present with sudden catastrophic neurologic events from hemorrhage into a tumor.


Prognosis and Prognostic Factors

The brain is the initial site of metastasis in 12-20% of patients. The average time between first diagnosis of a cutaneous primary and discovery of central nervous system (CNS) metastases is 45 months. Metastatic melanoma to the CNS is incurable. Treatment is aimed at tumor debulking, symptom relief, and palliation.

Relentless progression of clinical signs and symptoms is seen in most patients once they present with evidence of CNS disease. Median overall survival with brain metastases is about 16 weeks. [22] Average survival with meningeal involvement is about 8-16 weeks. [23]

The following are prognostic factors for CNS melanoma:

Tumor thickness and the presence of tumor ulceration are the single most important prognostic factors [12] ; the thicker the tumor, the worse the prognosis. Tumor thickness is measured from the stratum granulosum to the deepest dermal tumor cells. The presence of epidermal necrosis is also an adverse prognostic sign. Other negative prognostic factors include increased tumor vascularity, lymphovascular invasion, the presence of microsatellites, and concomitant visceral disease. High mitotic index and lack of tumor-infiltrating lymphocytes may also portend a poor prognosis.

Patients with solitary brain metastases, no lung or visceral metastases, and patients whose brain metastases were present upon diagnosis have a more favorable prognosis. [24]