Pigmented lesions of the CNS

Note:  This copy is for your personal, non-commercial use only To order presentation-ready copies for distribution to your colleagues, use the RadioGraphics Reprints form at the end of this article AFIP ARCHIVES 1503 From the Archives of the AFIP Pigmented Lesions of the Central Nervous System: Radiologic-Pathologic Correlation1 CME FEATURE See accompanying test at http:// www.rsna.org /education /rg_cme.html LEARNING OBJECTIVES FOR TEST After reading this article and taking the test, the reader will be able to: ■■Describe the clinical and pathologic features of pigmented lesions of the central nervous system (CNS) ■■Identify the imaging characteristics of pigmented lesions of the CNS ■■Discuss the differential diagnosis of pigmented lesions of the CNS TEACHING POINTS See last page Alice Boyd Smith, Lt Col, USAF MC • Elisabeth J Rushing, COL, MC, USA • James G Smirniotopoulos, MD Pigmented lesions of the central nervous system (CNS) are a diverse group of entities that run the gamut from benign to malignant These lesions may be well circumscribed or diffuse, and their imaging appearances are influenced by the degree of melanin content as well as the presence or absence of hemorrhage Pigmented lesions include primary melanocytic lesions of the CNS and metastatic melanoma, as well as other CNS neoplasms that may undergo melanization, including schwannoma, medulloblastoma, and some gliomas Primary melanocytic lesions of the CNS arise from melanocytes located within the leptomeninges, and this group includes diffuse melanocytosis and meningeal melanomatosis (seen in neurocutaneous melanosis), melanocytoma, and malignant melanoma Primary melanin-containing lesions of the CNS must be differentiated from metastatic melanoma because these lesions require different patient workup and therapy Absence of a known primary malignant melanoma helps in the differential diagnosis, but an occult primary lesion outside the CNS must be sought and excluded Pigmented lesions of the CNS are uncommon, and knowledge of their imaging characteristics and pathologic features is essential for their identification radiographics.rsna.org Abbreviations: CNS = central nervous system, CSF = cerebrospinal fluid RadioGraphics 2009; 29:1503–1524 • Published online 10.1148/rg.295095109 • Content Code: From the Departments of Radiologic Pathology (A.B.S.) and Neuropathology (E.J.R.), Armed Forces Institute of Pathology, Washington, DC; and Department of Radiology and Radiological Sciences, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814 (A.B.S., J.G.S.) Received May 6, 2009; revision requested June and received June 9; accepted June All authors have no financial relationships to disclose Address correspondence to A.B.S (e-mail: alsmith@usuhs.mil) The opinions or assertions contained herein are the private views of the authors and are not to be construed as official nor as reflecting the views of the Departments of the Army, Navy, or Defense 1504  September-October 2009 Introduction Teaching Point Teaching Point Melanocytes occur normally within the leptomeninges and are more concentrated at the base of the brain and on the ventral surface of the cervical spinal cord In these locations, pigmented leptomeninges may be visible macroscopically at surgery or autopsy The number of these melanocytes is generally comparable to that found in cutaneous pigmentation (1) Leptomeningeal melanocytes, like their cutaneous counterparts, are of neuroectodermal (neural crest) origin At magnetic resonance (MR) imaging, these pigmented foci frequently demonstrate T1 and T2 shortening, which is believed to be related to the presence of melanin; if hemorrhage is present, it may also contribute to this finding The imaging characteristics of melanin are thought to be caused by the presence of paramagnetic free radicals (indole semiquinones and semiquinones) (2,3) Interaction of the unpaired electrons in melanin with water protons results in dipoledipole interactions, which lead to the T1 and T2 shortening (4) Gebarski and Blaivas (1) demonstrated radiologic-pathologic correlation of leptomeningeal melanocytes by showing that these normal deposits of melanosomic melanin can occasionally be seen as areas of T2 hypointensity along the ventral aspect of the medulla oblongata where they tend to be most concentrated Occasionally, they noted that faint, spotty areas of T1-weighted hyperintensity were observed on normal images, but this finding did not correlate well with the pigmentation seen at pathologic evaluation (1) Infrequently, melanocytic lesions may arise from these normal melanocytes Melanocytic neoplasms of the central nervous system (CNS) are rare, and most frequently they are metastatic in origin Primary melanocytic lesions of the CNS may occur as discrete masses or diffuse proliferations and include neurocutaneous melanosis, meningeal melanocytoma, primary leptomeningeal melanomatosis, and melanoma It is important to differentiate primary melanincontaining lesions of the CNS from metastatic melanoma, because these lesions require a different patient workup and alternate therapeutic options The absence of a known primary malignant melanoma helps in the differential diagnosis; however, an occult primary lesion outside the CNS must be sought and excluded Other pigmented radiographics.rsna.org CNS lesions include neoplasms that may undergo melanization, such as schwannoma, medulloblastoma, and glioma, as well as melanocytic neuroectodermal tumor of infancy, a rare pigmented neoplasm that occurs in the first years of life In this article, we review the clinical, imaging, and pathologic findings of these rare lesions Neurocutaneous Melanosis Neurocutaneous melanosis is a rare congenital disorder characterized by the presence of large or multiple congenital melanocytic cutaneous nevi associated with intracranial leptomeningeal melanocytosis (5) It was first described in 1861 by Rokitansky, who reported a case of a 14-year-old girl with a congenital nevus and mental retardation who developed hydrocephalus (6) Since that time, approximately 100 cases of neurocutaneous melanosis have been reported in the literature (6) Most cases are sporadic; the disorder typically occurs in Caucasians, and there is an equal gender predilection (7,8) Deregulation of hepatocyte growth factor/scatter factor, a cytokine that stimulates the proliferation, migration, and morphogenesis of cultured epithelial cells, has been implicated in the pathogenesis of the disorder because of its role in the distribution and proliferation of melanocytes (6,9) Current evidence indicates that neurocutaneous melanosis is a phakomatosis that results from congenital dysplasia of the neuroectodermal melanocyte precursor cells, leading to proliferation of melanin-producing cells in the skin and leptomeninges (10) Neurocutaneous melanosis has been reported to be associated with other neurocutaneous syndromes such as Sturge-Weber syndrome (11,12) An association with Dandy-Walker malformation (hypoplasia or absence of the cerebellar vermis, hypoplasia of cerebellar hemispheres, large fourth ventricle, and large posterior fossa) has been reported in 8%–10% of children with neurocutaneous melanosis (13) The exact pathogenesis for this association is unknown, but some suggest that obstruction of the fourth ventricle by melanocytes may play a role, or that associated leptomeningeal anomalies affect the development of the cerebellum and fourth ventricle (14) However, the most widely accepted hypothesis is that leptomeningeal melanosis interferes with the inductive effects of primitive meningeal cells on deposition of extracellular matrix, neuronal migration, and formation of the normal basal cerebrospinal fluid (CSF) resorption pathways (15,16) The prognosis RG  ■  Volume 29  •  Number Figure 1.  Photograph shows a newborn infant with a giant congenital nevus that involves the back, with multiple smaller satellite nevi for patients with Dandy-Walker malformation and neurocutaneous melanosis is extremely poor, with all reported patients dying by years of age from malignant transformation of the melanosis (15) The leptomeningeal involvement in neurocutaneous melanosis differs from that seen in primary melanoma of the meninges, which results in focal pigmented lesions of the leptomeninges The dura mater is not typically affected, but involvement of the cerebral parenchyma, choroid plexus, and ventricular ependyma has been reported (17) Parenchymal melanin deposits most likely represent melanocytes tracking along the perivascular spaces The anterior temporal lobe, particularly in the region of the amygdala, is the most frequent location for parenchymal melanocytic accumulation Other sites include the cerebellum, thalami, and base of the frontal lobe (5,17) Patients with neurocutaneous melanosis have multiple (more than three) pigmented nevi on the head, neck, or dorsal spine, and two-thirds of patients have a giant congenital “bathing trunk” melanocytic nevus that typically affects the lumbosacral region (Fig 1) (18) Giant congenital nevi occur in approximately one in 20,000 newborns and are defined as those that are ex- Smith et al  1505 pected to grow to a diameter of at least 20 cm in adulthood (19) Six percent to 11% of patients with giant congenital nevi develop symptomatic neurocutaneous melanosis, and those with nevi involving the head, posterior neck, or paravertebral area are at the greatest risk (20,21) These patients are also at risk for developing leptomeningeal melanoma and cutaneous melanoma (22) Fox (23) proposed the original diagnostic criteria for neurocutaneous melanosis in 1972 Kadonaga and Frieden (24) revised the criteria, which are as follows: large (currently or estimated to become no less than 20 cm in diameter in adults or 6–9 cm in infants) or multiple (≥ three) congenital nevi associated with meningeal melanosis or CNS melanoma; no evidence of cutaneous melanoma; and no evidence of meningeal melanoma except in patients whose skin examination reveals no malignant lesions In the first years of life, patients with neurocutaneous melanosis typically develop neurologic manifestations related to increased intracranial pressure or seizures In rare cases, symptoms begin in adulthood, and some patients remain asymptomatic (19,25,26) Hydrocephalus occurs in the majority of patients and is related to either meningeal thickening or CSF outflow obstruction or decreased CSF reabsorption (7,17) Other reported complications include subdural or parenchymal hemorrhage, syringomyelia, and spinal arachnoiditis (7) Approximately 20% of patients have spinal involvement and develop symptoms of myelopathy, radiculopathy, or bowel or bladder dysfunction (6) A second, smaller peak of symptom development occurs during puberty or the young adult years (6) Patients who present later in life may manifest with neuropsychiatric symptoms, including depression and psychosis (14) The development of benign melanocytic proliferation of the leptomeninges has a poor prognosis, and neither radiation therapy nor chemotherapy improves the patient outcome (16) Patients with neurocutaneous melanosis are reported to develop malignant melanoma in approximately 40%–60% of cases (23).) Faillace et al (27) have suggested that malignant transformation is heralded by development of intraparenchymal invasion or intracranial or intraspinal masses The majority of patients die within years from benign overgrowth of melanocytic cells or development of malignant melanoma (6) radiographics.rsna.org 1506  September-October 2009 Figure 2.  Neurocutaneous melanosis (a) Photograph of the whole brain and upper spinal cord shows diffuse brown pigmentation (b) Photomicrograph (original magnification, ×120; hematoxylin-eosin stain) reveals that the leptomeninges are populated by a neoplastic spindle cell proliferation containing melanin (arrows) Figure 3.  Neurocutaneous melanosis in a 2-year-old boy with a history of seizure disorder (a) Precontrast axial CT image demonstrates an area of mild hyperattenuation along the left Sylvian fissure (arrow) The patient also had hydrocephalus and a ventriculoperitoneal shunt was recently placed (airfluid level in ventricle) (b) Postcontrast axial CT image reveals leptomeningeal enhancement Pathologic and Histologic Features Gross examination of the brain reveals dense black-brown discoloration overlying the affected surfaces (Fig 2a), and areas of localized lesions may demonstrate nodularity At histologic examination, neurocutaneous melanosis resembles cutaneous nevi, with polygonal cells with prominent nucleoli and cytoplasmic melanin (Fig 2b) Invasion of the Virchow-Robin spaces is noted (23) Results of immunohistochemical staining are also similar to those for cutaneous melanocytic lesions: negative for keratins or other epithelial or glial markers and positive for S-100 protein (the marker for melanocytic and neuroepithelial differentiation) and HMB-45 (the marker for melanocytic differentiation) Imaging Appearance Computed tomography (CT) is not optimal, compared with MR imaging, for demonstrating neurocutaneous melanosis The foci of melanincontaining cells may appear only as subtle areas of high attenuation They are difficult to visualize on CT images unless conversion to melanoma has occurred (Fig 3a) Hydrocephalus may be present and is thought to occur when extensive melanosis is present Leptomeningeal enhancement may be seen on postcontrast CT images (ie, obtained after administration of contrast material) (6) (Fig 3b) RG  ■  Volume 29  •  Number Smith et al  1507 Figure 4.  Neurocutaneous melanosis in a 14-year-old boy with transient palsies of the seventh and eighth cranial nerves (a) Axial T1-weighted image demonstrates T1 shortening (arrows) in both medial temporal lobes (b) Postcontrast axial T1-weighted image shows linear enhancement of the leptomeninges that is best seen along the midbrain (c) Coronal fluid-attenuated inversion recovery (FLAIR) image demonstrates high signal intensity in the sulci (arrowheads) and in the bilateral amygdalae (arrows) (d) Sagittal T2-weighted image of the cervical and thoracic spine demonstrates an arachnoid cyst (arrow) at the level of the midthoracic spine MR imaging findings of neurocutaneous melanosis include foci (typically cm or less in size) of T1 shortening within the brain parenchyma and meninges These foci are most commonly found in the anterior temporal lobe (especially in the region of the amygdala), cerebellar white matter, cerebellar nuclei, and the brainstem (Fig 4a) Leptomeningeal enhancement has been reported in cases of neurocutaneous melanosis (Fig 4b) and, when associated with hydrocephalus, may suggest diffuse leptomeningeal spread (5,17,28,29) The presence of leptomeningeal or intraparenchymal 1508  September-October 2009 radiographics.rsna.org Figure 5.  Neurocutaneous melanosis in a 14-month-old boy with a history of congenital hairy nevus (same patient as in Fig 1) and Dandy-Walker syndrome Postcontrast sagittal T1-weighted image demonstrates extensive leptomeningeal enhancement and an enhancing mass (*) in the posterior fossa, findings consistent with degeneration to malignant melanoma Note that the brainstem is compressed against the clivus (arrow) because of the posterior fossa cyst and the enhancing mass Figure 6.  Melanocytoma in a 37-year-old man with headaches (a, b) Axial T1-weighted (a) and axial T2-weighted (b) images demonstrate a solitary mass lesion that involves the posterior fossa and Meckle cave; the mass exhibits T1 and T2 shortening (c) Postcontrast T1-weighted image shows avid enhancement of the lesion (d) Intraoperative photograph reveals the darkly pigmented lesion RG  ■  Volume 29  •  Number Smith et al  1509 Figure 7.  Intramedullary melanocytoma in a 59-year-old man with numbness in his right arm for months (a) Sagittal T2-weighted image demonstrates an intramedullary lesion with T2 shortening at the level of C2-3, with surrounding edema and hydrosyringomyelia (b) Sagittal T1-weighted image without contrast material enhancement shows T1 shortening within the lesion (c) Intraoperative photograph shows the darkly pigmented, intramedullary lesion Teaching Point lesion enhancement has been thought to correlate with malignant degeneration; however, at least one report has contradicted this hypothesis, and some authors have suggested that focal nodular or thick plaquelike enhancement may be more indicative of malignant degeneration (15,28) If malignant melanoma develops, a mass lesion may be seen Hayashi et al (30) reported a case in which leptomeningeal hyperintensity was seen on the T2 FLAIR images; the authors speculated that either the high protein concentration within the CSF or the T1 shortening effect of malignant melanoma may contribute to the observed hyperintensity The parenchymal foci may also appear hyperintense on T2 FLAIR images (Fig 4c) (30) Hypoplasia of the cerebellum and pons may be seen and is usually associated with melanosis in these locations (5,31) Associated spinal and intracranial arachnoid cysts and spinal lipomas have been described (Fig 4d) (32,33) Degeneration into malignant melanoma is indicated by progressive growth, surrounding vasogenic edema or mass effect, or development of central necrosis (Fig 5) (5) Meningeal Melanocytoma Meningeal melanocytomas are rare, pigmented, slow-growing, and typically benign neoplasms that arise from the normal melanocytic cells of the leptomeninges; however, malignant behavior of these tumors has been reported (34) Limas and Tio (35) first described these lesions in 1972; before this, they were referred to as melanotic meningioma Approximately 110 cases of meningeal melanocytoma have been reported (34,36) The annual incidence of meningeal melanocytoma is estimated to be one case per 10 million population, and females are affected more often than males (37) Meningeal melanocytomas may manifest at any age, but most patients are in the 5th decade of life The clinical signs and symptoms associated with these lesions depend on their location and include myelopathy, radiculopathy, cranial nerve deficits, seizures, and hydrocephalus (34) Meningeal melanocytomas are predominantly located in the posterior cranial fossa, Meckle cave, or cervical and thoracic spinal canal, probably because of the normally higher density of melanocytes in these locations (Fig 6) These tumors are usually solitary (38) In rare cases, spinal intramedullary tumors are observed (Fig 7) Supratentorial lesions also are rare, with approximately 25 cases reported in the literature (39) A thorough physical examination of the patient is required to rule out a primary cutaneous, ocular, or mucosal melanoma, especially because the histologic characteristics of melanocytoma and melanoma overlap 1510  September-October 2009 Figure 8.  Melanocytoma in a 64-yearold woman with a 2-week history of right-sided headaches (a) Photograph of a gross specimen demonstrates a well-circumscribed, reddish-brown lesion with a dural attachment (arrow) (b) Photomicrograph (original magnification, ×200; hematoxylin-eosin stain) shows a cellular neoplasm with the cells arranged in “nests” (arrows) Mitotic figures are absent, and no pigmentation is seen (c) Axial nonenhanced CT image reveals an extraaxial lesion of iso- to slightly hyperattenuation relative to gray matter The lesion contains a focal area of low attenuation, a finding suggestive of cystic degeneration (d) Axial T2-weighted image shows the heterogeneous extraaxial mass with a large focus of T2 prolongation, suggestive of cystic degeneration (e) Coronal T1-weighted image demonstrates the cystic region with a focus of T1 shortening medial to it, an appearance that most likely represents melanin (f) Postcontrast T1weighted image shows avid enhancement of the solid portion of the mass radiographics.rsna.org RG  ■  Volume 29  •  Number Complete surgical resection may be curative, but in up to 22% of cases lesions recur within years after surgery, even if complete resection is achieved (40) Without complete resection, the recurrence rate is even higher: up to 50% of cases (40) Radiation therapy is reserved for cases in which complete resection is not possible or in which there is a recurrence (40) There have been reports of melanocytomas transforming into malignant melanoma, spreading along the leptomeninges, and even demonstrating distant metastasis (34,41–43) Pathologic and Histologic Features At gross examination, most meningeal melanocytomas appear black, but red, white, tan, brown, and blue lesions have been observed (44) Melanocytomas tend to compress rather than infiltrate the adjacent tissues; however, parenchymal invasion has been reported in cases of intermediate malignancy (45) Because these lesions are based on the meninges, meningeal melanocytomas may be mistaken for meningioma at gross inspection At microscopic examination, they may demonstrate tight cellular nests or whorls (Fig 8a, 8b), similar to those seen in meningiomas; in fact, in the past, these lesions were referred to as melanotic meningioma (45) Use of electron microscopy and immunoperoxidase staining is helpful in differentiating between melanocytoma and meningioma (46) Electron microscopy, although not routinely used for tumor diagnosis, demonstrates the absence of desmosomes and interdigitating cellular processes that are found in meningiomas; it can also reveal the presence of melanosomes Immunohistochemical analysis demonstrates the expression of melanocytic marker proteins (such as S-100, melan A, and HMB-45) but an absence of meningothelial cell markers (such as EMA) (47) Meningeal melanocytomas are histologically characterized as cellular lesions, and the cytoplasm contains variable amounts of melanin pig- Smith et al  1511 ment in intracellular granules Amelanotic examples are reported The important histologic differential diagnoses of meningeal melanocytoma are melanotic schwannoma and malignant melanoma The differentiation of melanocytoma from melanoma can be difficult The lack of mitotic activity, nuclear pleomorphism, and hyperchromaticity, as well as an indolent growth pattern spanning more than years, are all characteristics that indicate a melanocytoma rather than a melanoma (10) However, a small subset of meningeal melanocytic tumors may be difficult to classify as either a melanocytoma or a malignant melanoma because they demonstrate intermediate histologic features (45) In such cases, a designation such as “melanocytic neoplasm of indeterminate biologic potential” is sometimes applied Imaging Appearance At CT, meningeal melanocytoma manifests as an extraaxial iso- to hyperattenuating lesion that enhances after administration of contrast material, an imaging appearance similar to that of meningiomas Unlike meningioma, however, meningeal melancytoma rarely manifests with tumor calcification and hyperostosis of the adjacent bone (38) At MR imaging, these lesions typically demonstrate isointensity to hyperintensity with T1-weighted pulse sequences and hypointensity or isointensity with T2-weighted pulse sequences, and they enhance homogeneously after administration of gadolinium (44,48,49) (Figs 8, 9) The variable signal intensity most likely is related to the varying amounts of melanin within lesions, but it may also be caused by intratumoral hemorrhages (46) MR imaging does not allow melanocytomas to be reliably distinguished from other extraaxial neoplasms, such as meningiomas, schwannomas, and malignant melanoma, which occur in similar locations (Fig 9) Teaching Point 1512  September-October 2009 Figure 9.  Melanocytoma in a 23-yearold woman with headaches (a) Axial T1weighted image demonstrates a lesion in the middle cranial fossa, with mass effect on the midbrain and intrinsic T1 shortening involving the lateral portion of the lesion The medial portion is isointense relative to gray matter (b) On the axial T2-weighted image, the lesion is slightly iso- to hypointense and has a mild degree of surrounding edema within the adjacent temporal lobe (c) Postcontrast T1-weighted image demonstrates relatively avid enhancement of the mass and a dural tail (arrow) Figure 10.  Primary leptomeningeal melanomatosis in a 32-year-old man with a 1-week history of nausea, vomiting, and headaches (a) Photograph of the cauda equina demonstrates diffuse black staining of the leptomeninges (b) Photograph of a cross section of the cauda equina demonstrates cells with brown pigmentation surrounding the nerve roots (*) (c) Sagittal postcontrast T1-weighted image of the spine shows diffuse enhancement along the cauda equina (arrows) radiographics.rsna.org RG  ■  Volume 29  •  Number Primary Leptomeningeal Melanomatosis Primary leptomeningeal melanomatosis is a rare, aggressive neoplasm of the CNS that arises from melanocytes within the leptomeninges and carries a poor prognosis It is also referred to as a meningeal variant of primary malignant melanoma The malignant melanocytes spread in the leptomeninges, into the Virchow-Robin spaces, and superficially within the brain substance The first case of diffuse leptomeningeal melanomatosis was described by Virchow in 1859 (50) Primary leptomeningeal melanomatosis is more common in adults (peak prevalence, 4th decade of life) than in children, and patients present with variable signs and symptoms including seizures, signs of increased intracranial pressure, psychiatric disturbances, cranial nerve palsies, and spinal cord compression (50,51) The ante mortem diagnosis of primary leptomeningeal melanomatosis can be challenging, because it may be difficult to recognize on radiologic images, and the isolated tumor cells within the CSF may be hard to recognize at cytologic analysis (52,53) Smith et al  1513 weighted images Intense enhancement is seen on the postcontrast images (Fig 10c) The differential diagnosis for these imaging findings includes meningeal carcinomatosis, meningitis, and idiopathic hypertrophic pachymeningitis Primary Malignant Melanoma of the CNS At examination of the gross specimen, diffuse darkening and thickening of the leptomeninges is noted (Fig 10a) Primary leptomeningeal melanomatosis can histologically mimic a variety of other lesions, including brain metastasis from a malignant melanoma elsewhere in the body (54) Polygonal neoplastic cells with cytoplasmic pigment and nuclei containing prominent nucleoli are noted (Fig 10b) The diffuse growth pattern of this neoplasm, as opposed to the localized lesions found in metastatic melanoma, and the absence of malignant melanoma elsewhere in the body assist in making the diagnosis Primary malignant melanoma of the CNS accounts for approximately 1% of all melanoma cases (55) The lesion occurs most frequently in adults (mean age, 50 years), particularly men (56) Primary malignant melanoma most often develops within the leptomeninges, a site that reflects the common neural crest origin of both melanocytes and meningothelial cells (57) Primary malignant melanoma arising within the ventricles has been reported; the atypical site may be due to arrested migration of melanocytic cells whereby they are deposited within the pia mater From their location within the pia mater, melanocytes may be incorporated into the choroid plexus (4) Spinal melanoma is extremely rare, and most cases are intradural or have both intra- and extradural components (3,58) The diagnosis of a primary CNS melanoma is based on the absence of any other melanoma, both outside the CNS and in other CNS sites (55) The prognosis for patients with primary malignant melanoma of the CNS is better than that for those with metastatic melanoma, with reports of survival up to 12 years after presentation; however, the prognosis worsens with the presence of leptomeningeal spread (44,59,60) Recurrence after surgery tends to be localized and distant metastases are rare (44,59) The usefulness of chemotherapy, radiation therapy, and immunotherapy in the treatment of these lesions has not been clearly established (59) Imaging Appearance Pathologic and Histologic Features CT and MR imaging reveal diffuse thickening of the leptomeninges, with abnormal enhancement on the postcontrast images On T1-weighted images, the regions of melanocytosis may be isointense or hyperintense from T1 shortening due to the paramagnetic properties of the melanin, and they are correspondingly hypointense on T2- Primary malignant melanoma is typically a darkly pigmented neoplasm (Fig 11a) Histologic evaluation reveals a highly cellular tumor with the cells Pathologic and Histologic Features 1514  September-October 2009 radiographics.rsna.org Figure 11.  Primary meningeal melanoma in a 34-yearold woman with headaches and right-sided neck pain (a) Photograph of the gross specimen demonstrates a predominantly darkly pigmented lesion with a central area that is unpigmented (b) Photomicrograph (original magnification, ×200; hematoxylineosin stain) reveals that the tumor is composed of sheets of pleomorphic cells with prominent nucleoli Some of the neoplastic cells contain melanin pigment (arrow) (c) Sagittal T1-weighted image shows a lesion centered in the region of the foramen magnum that has scattered areas of T1 shortening (arrows) (d) On the postcontrast image, the lesion is enhanced arranged in sheets Pleomorphic cells with abundant cytoplasm and dark pigmentation are noted, although amelanotic examples have been observed (Fig 11b) Nuclear pleomorphism, mitoses, and prominent nucleoli are also seen Imaging Appearance As with melanocytic lesions elsewhere, primary malignant melanoma varies in its imaging features, based on the degree of melanocytic content (61) and the presence or absence of hemorrhage Typically, these lesions demonstrate some degree of both T1 and T2 shortening and enhancement on postcontrast images (Fig 11c, 11d) The enhancement pattern is typically homogeneous, but it may be inhomogeneous, peripheral, or nodular (58) Unfortunately, there are no distinguishing imaging characteristics to separate primary malignant melanoma from other melanocytic lesions of the CNS (3) The imaging findings of primary malignant melanoma of the CNS are similar to those of metastatic melanoma; therefore, careful examination of the patient for the presence of melanoma involving the skin, eyes, and mucosal surfaces is necessary to exclude a primary lesion (61) Melanotic Schwannoma Melanotic schwannomas are rare lesions, with only about 80 cases reported in the literature (62,63) They have been described as neoplasms with features intermediate between those of schwannoma and malignant melanoma (64) Both melanocytes and Schwann cells are derived from neuroectoderm Several theories for the etiology of melanotic schwannomas have been proposed, including the melanomatous transformation of neoplastic Schwann cells, phagocytosis of melanin by Schwann cells, and the simultaneous presence of two distinct neoplastic populations of proliferating melanocytes and Schwann cells (65,66) Two forms of melanotic schwannoma are described: sporadic and psammomatous (67) Psammomatous melanotic schwannoma is associated with Carney complex, which consists of myxomas (of the heart, breast, and skin), spotty pigmentation, and endocrinopathy (Cushing syndrome, precocious puberty, and acromegaly) (68) RG  ■  Volume 29  •  Number Smith et al  1515 Figure 12.  Metastatic melanotic schwannoma in a 69-year-old man with palsies of the right fifth, sixth, and seventh cranial nerves (a) Postcontrast CT image reveals an enhancing lesion in the right aspect of the pons Enhancement extends anteriorly along the second division of the trigeminal nerve into the cavernous sinus and infraorbital foramen (arrows) (b) Photograph of the gross specimen demonstrates a darkly pigmented lesion involving the right aspect of the pons (c) Photomicrograph (original magnification, ×120; hematoxylin-eosin stain) shows that the spindle cell neoplasm contains numerous pigment-laden cells (arrows) The patient also had metastatic lesions involving the lungs and mandible Melanotic schwannomas typically occur in patients a decade younger than those with other types of schwannomas, with peak prevalence in the 4th decade of life (age range, 10–92 years) Patients usually present with symptoms of nerve compression (63) These lesions are more typically intracranial, but they also occur within the spinal canal (69) When they develop within the spine, the tumors most often arise in the thoracic region and they may be intramedullary (70) Twenty percent of patients will have multiple melanotic schwannomas The behavior of these tumors is typically benign, but 10% of melanotic schwannomas will undergo malignant degeneration (63) Metastasis and meningeal seeding have been reported but are exceedingly rare (Fig 12) (64) Treatment consists of surgical resection, and the prognosis is typically excellent if complete resection is achieved (69) In a review by Killen et al (71), 24% of all melanotic schwannomas were noted to recur, and patients with tumors associated with the cranial nerves had the worst prognosis Pathologic and Histologic Features At gross examination, the melanin content of the melanotic schwannoma imparts a dark blue, purple, or black appearance These tumors are usually well circumscribed and may contain areas of hemorrhage Results from immunohistochemical staining help secure the diagnosis Histologic examination reveals spindle-shaped Schwann cells in combination with melanosomes of various stages of maturation (63) Psammoma bodies, melanin, and fat can be seen in the psammomatous form of melanotic schwannoma (72) These lesions stain positive for S-100 protein and vimentin, and they stain variably with glial fibrillary acid protein, HMB-45, and other melanocytic markers Imaging Appearance At CT, melanotic schwannoma manifests as a hyperattenuating lesion, which may have areas of calcification (Fig 13a) At MR imaging, melanotic schwannomas, unlike other pigmented lesions, radiographics.rsna.org 1516  September-October 2009 Figure 13.  Melanotic schwannoma in a 24-year-old woman with Carney complex and complaints of low back pain (a) Nonenhanced CT image demonstrates a hyperattenuating lesion that expands the right sacral foramina Focal areas of calcification are present (arrow) (b) Axial T1-weighted image shows that the mass is isointense relative to muscle No T1 shortening is present (c) Axial T2-weighted image demonstrates variable signal intensity within the lesion, which contains areas of hyperintensity are hypointense to isointense with T1-weighted pulse sequences and isointense to slightly hyperintense with T2-weighted pulse sequences (Fig 13b, 13c) However, their signal characteristics vary, and areas of T1 and T2 prolongation may be seen (Fig 14) (73) On postcontrast images, the enhancement pattern of the lesions varies Other CNS Lesions with Pigmentation Several other CNS tumors may demonstrate melanocytic differentiation in rare cases Medulloblastomas are among the more common of these lesions, and a melanocytic variant was included in the 2007 World Health Organization report (74) Melanocytic differentiation of lowgrade glial neoplasms has been reported, as well as one case report of a gliosarcoma with melanocytic differentiation (75) In rare cases, craniopharyngiomas may contain melanin (76) Metastasis of melanoma to a preexisting intracranial neoplasm is exceedingly rare, with only two cases reported in the literature (34) Melanocytes in pigmented neoplasms, such as teratoma, tend to be more dispersed, whereas pigmentation secondary to a metastatic melanoma is more likely to be focal (Fig 15) Melanoma Metastases The CNS is a common site of metastases from malignant melanoma, which is the third most common neoplasm (after lung and breast cancers) to metastasize to the brain (78) In patients with metastatic melanoma, 39% have brain metastases, as reported at autopsy (79) The majority of patients have multiple lesions, and the cerebrum is a more common location than the cerebellum (79) In some cases, the primary tumor remains undetectable, and thus the CNS metastases are difficult to differentiate from primary CNS melanoma, but the primary form is much less common that the metastatic form (4) Patients with melanoma metastatic to the CNS have a poor prognosis, with a median survival of 113 days after discovery (80) Pathologic and Histologic Features Metastatic melanoma displays a spectrum of morphologic features, ranging from spindled to epithelioid cells, and may show variable pigmentation (Fig 16) Melanomas that lack pigmentation at light microscopic examination may pose RG  ■  Volume 29  •  Number Smith et al  1517 Figure 14.  Melanotic schwannoma in a 53-year-old woman with headaches (a) Sagittal T1-weighted image demonstrates a hyperintense lesion anterior to the medulla (b) Axial T2weighted image reveals heterogeneous signal within the lesion (arrow) The T2 prolongation in the left cerebellar hemisphere is the result of a previous unrelated surgery Figure 15.  Teratoma in a 19-month-old boy with a history of multiple generalized seizures (a) Axial T1-weighted image demonstrates a lesion that originates from the pineal region and that contains scattered areas of T1 prolongation (arrow) Hydrocephalus is present (b) On the T2-weighted image, the lesion appears heterogeneous (c) Photograph of the gross specimen reveals scattered areas of pigmentation throughout the lesion (arrows) radiographics.rsna.org 1518  September-October 2009 Figure 16.  Metastatic melanoma in a 58-year-old man with seizures (a) Photograph of a gross specimen reveals numerous darkly pigmented lesions located predominantly at the gray-white matter junction (b) Photomicrograph (original magnification, ×200; hematoxylin-eosin stain) reveals nests of tumor cells with areas of melanin pigment (arrows) Figure 17.  Metastatic melanoma in a 63-year-old man with a 3-week history of ataxia and memory loss Postcontrast CT image reveals several enhancing lesions with surrounding vasogenic edema at the graywhite matter junction; one in the right frontal lobe shows hemorrhage (arrow) a particular diagnostic challenge Cytologic features are sometimes helpful in alerting the pathologist to consider this entity The neoplastic cells often possess prominent nucleoli, a finding that should prompt immunohistologic study to confirm the diagnosis Marked cellular and nuclear atypia, a high mitotic activity, and necrosis are seen These lesions are likely to hemorrhage Figure 18.  Metastatic melanoma in a 17-year-old boy with a history of melanoma involving the anterior chest wall Postcontrast CT image demonstrates numerous enhancing subependymal lesions (arrows) Imaging Appearance Similar to other metastases, multiple foci of metastatic melanoma are predominantly located at the gray-white matter junction and have surrounding vasogenic edema Enhancement is seen on postcontrast images The tendency of metastatic melanoma to hemorrhage also affects imaging characteristics (Fig 17) The differential diagnosis for hemorrhagic metastatic lesions in the CNS includes breast cancer, lung cancer, choriocarcinoma, thyroid cancer, RG  ■  Volume 29  •  Number Smith et al  1519 Figure 19.  Metastatic melanoma in a 32year-old woman with headaches (a) Coronal T1-weighted image demonstrates a hyperintense sellar mass that superiorly displaces the optic chiasm (arrow) (b) Coronal T2weighted image reveals the hypointense lesion (arrow) (c) Photomicrograph (original magnification, ×200; hematoxylin-eosin stain) of a sectioned specimen demonstrates melanincontaining cells and renal cell cancer (81) At CT, in the absence of hemorrhage, the lesions may be iso- to hyperattenuating Attempts have been made to characterize the MR imaging patterns of metastatic melanoma as melanotic or amelanotic For melanotic melanoma, the expected pattern is hyperintensity relative to cortex on T1-weighted images and hypointensity relative to cortex on T2-weighted images The pattern for amelanotic melanoma is similar to that of other brain neoplasms, with hypo- to isointensity on T1-weighted images and iso- to hyperintensity relative to cortex on T2-weighted images However, this pattern approach is an oversimplification, and the amount of melanin-containing cells in metastases is extremely variable It has been postulated that intralesional hemorrhage plays a greater role in influencing the imaging appearance of melanoma than does the melanin content (2) Isiklar et al (78) found that 24% (ten) of 42 lesions had the typical melanotic imaging pattern, and all ten contained melanin They noted that tumors with more than 10% melanin-containing cells revealed the melanotic MR imaging pattern They postulated that blood products could have attributed to the melanotic imaging pattern; however, they did not believe that blood products were the dominant influence on signal characteristics in all cases In evaluating the amelanotic lesions, Isiklar et al (78) found that over half of the tumors (10 of 16) that appeared “amelanotic” at imaging actually contained melanin (as confirmed with histologic analysis), although nine of the 10 had less than 10% melanin-containing cells A review of studies in which imaging appearances of melanoma Teaching were evaluated provides no clear consensus as Point to whether the imaging findings are more influenced by paramagnetic effects of melanin or by blood products or by a combination of both (2,78,82) In addition, melanoma may manifest imaging characteristics that not follow either the melanotic or amelanotic patterns In a study of metastatic melanoma in the cerebellopontine angle and internal auditory canals (a rare location, with less than 10 reported cases), Arriaga et al (83) found that these lesions were isointense on T1-weighted images and hyperintense on T2-weighted images, in which case the differential diagnosis included meningioma (83) The imaging patterns of metastatic melanoma may also vary depending on anatomic location Most patients have multiple lesions, with the cerebral hemispheres being the most common site (79) A miliary pattern of brain metastasis has been reported, and subependymal spread may be seen as well (84,85) (Fig 18) In rare cases, metastases of melanoma can also occur in the choroid plexus and pituitary gland (79) (Fig 19) In 1520  September-October 2009 Figure 20.  Melanotic neuroectodermal tumor of infancy in a 14-month-old girl with new onset of a seizure disorder (a) Photograph of a cross-sectioned gross specimen reveals areas containing melanin (arrow) (b) Photomicrograph (original magnification, ×120; hematoxylineosin stain) of a sectioned specimen shows tumor cells with abundant eosinophilic cytoplasm, some of which contain melanin (arrows) (c) Axial nonenhanced CT image (produced with bone algorithm) demonstrates marked hyperostosis in the left parietal region (d) Axial nonenhanced CT image shows a hyperattenuating mass adjacent to the hyperostosis (arrows) (e) Axial T2-weighted image demonstrates the hyperostosis as well as the soft-tissue mass, which is slightly hyperintense relative to gray matter Mild intraparenchymal edema is seen adjacent to the lesion (f) Postcontrast T1weighted image demonstrates enhancement of the softtissue component radiographics.rsna.org RG  ■  Volume 29  •  Number a study of 105 patients with stage III melanoma, Das Gupta and Brasfield (79) described only one patient with a metastasis to the choroid plexus Melanotic Neuroectodermal Tumor of Infancy Melanocytic neuroectodermal tumor of infancy is a rare condition that affects newborns and infants The neoplasm was first described in 1918 by Krompecker, who described it as a melanocarcinoma (86) Its histogenesis is uncertain, but melanocytic neuroectodermal tumor is thought to have a neural crest origin (87) These lesions are believed to represent a dysembryogenic neoplasm that arises from the neural crest cells, based on findings from ultrastructural, immunohistochemical, electron microscopic, and molecular genetic studies (88,89) The neural crest origin of this tumor is further supported by its secretion of vanillylmandelic acid or other catecholamines This finding is also observed in other neoplasms of neural crest origin such as pheochromocytomas, ganglioneuroblastoma, and neuroblastoma (89,90) Melanocytic neuroectodermal tumors are reported to be more common in boys than in girls, and greater than 90% occur in children less than year old (91–93) Most frequently, melanocytic neuroectodermal tumor arises in the anterior aspect of the maxilla (60% of cases), but it can involve the skull (10.8% of cases, usually in the region of the anterior fontanelle), dura mater, and brain (4.3%) (94,95) It has also been observed within the epididymis, femur, mediastinum, and ovary (87) The majority of these neoplasms are slowgrowing, benign tumors that have a 2% chance of malignant degeneration Even though it is a benign neoplasm, melanocytic neuroectodermal tumor is frequently worrisome clinically because of its rapid onset and growth rate Most patients with melanocytic neuroectodermal tumor are cured with complete resection of the mass, but local recurrence rates of 15%–45% have been reported (96) Pathologic and Histologic Features At gross inspection, melanocytic neuroectodermal tumors appear well circumscribed but not encapsulated (Fig 20a) Histopathologic examination demonstrates a unique biphasic pattern with larger pigmented melanocyte-like cells and smaller nonpigmented neuroblast-like cells arranged in a background of fibrous connective tissue stroma (Fig 20b) At immunohistochemical analysis, specimens stain positive for cytokeratin, synaptophysin, glial fibrillary acidic protein, and Leu-7 They are usually negative for S-100 protein (97) Smith et al  1521 Imaging Appearance Imaging of melanocytic neuroectodermal tumor of infancy when it involves the brain, skull, or dura mater may reveal tumoral calcification and calvarial hyperostosis, which is best visualized with CT (Fig 20c, 20d) At MR imaging, the lesions tend to be isointense relative to brain with T1-weighted pulse sequences and isointense to hyperintense with T2-weighted pulse sequences (Fig 20e); however, they may demonstrate areas of T1 and T2 shortening, findings that may reflect the intratumoral melanin (96) Enhancement occurs on postcontrast images and is typically marked (Fig 20f) Conclusions Pigmented lesions of the CNS are rare entities that may appear similar to other CNS neoplasms at both imaging and histologic evaluation Metastatic melanoma should be ruled out when many of these lesions are encountered, since the prognosis and therapeutic options for pigmented lesions differ substantially from what is expected for melanoma Knowledge of the clinical and pathologic spectrum of these lesions aids in the differentiation of these neoplasms from other more common entities that may have overlapping imaging features References Gebarski SS, Blaivas MA 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Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;93(6):688–698 94 Selim H, Shaheen S, Barakat K, Selim AA Melanotic neuroectodermal tumor of infancy: review of literature and case report J Pediatr Surg 2008;43 (6):E25–E29 95 Cutler LS, Chaudhry AP, Topazian R Melanotic neuroectodermal tumor of infancy: an ultrastructural study, literature review, and reevaluation Cancer 1981;48(2):257–270 96 Jeon HJ, Kong DS, Shin HJ Melanotic neuroectodermal tumor of infancy: a case report Childs Nerv Syst 2008;24(12):1489–1492 97 Nelson ZL, Newman L, Loukota RA, Williams DM Melanotic neuroectodermal tumour of infancy: an immunohistochemical and ultrastructural study Br J Oral Maxillofac Surg 1995;33(6):375–380 This article meets the criteria for 1.0 credit hour in category of the AMA Physician’s Recognition Award To obtain credit, see accompanying test at http://www.rsna.org/education/rg_cme.html RG Volume 29 Number September-October 2009 Smith et al From the Archives of the AFIP: Pigmented Lesions of the Central Nervous System: Radiologic-Pathologic Correlation Alice Boyd Smith, Lt Col, USAF MC, et al RadioGraphics 2009; 29:1503–1524 • Published online 10.1148/rg.295095109 • Content Code: Page 1504 Melanocytes occur normally within the leptomeninges and are more concentrated at the base of the brain and on the ventral surface of the cervical spinal cord Page 1504 It is important to differentiate primary melanin-containing lesions of the CNS from metastatic melanoma, because these lesions require a different patient workup and alternate therapeutic options The absence of a known primary malignant melanoma helps in the differential diagnosis; however, an occult primary lesion outside the CNS must be sought and excluded Page 1509 Degeneration into malignant melanoma is indicated by progressive growth, surrounding vasogenic edema or mass effect, or development of central necrosis Page 1511 The lack of mitotic activity, nuclear pleomorphism, and hyperchromaticity, as well as an indolent growth pattern spanning more than years, are all characteristics that indicate a melanocytoma rather than a melanoma Page 1519 A review of studies in which imaging appearances of melanoma were evaluated provides no clear consensus as to whether the imaging findings are more influenced by the paramagnetic effects of melanin or by blood products or by a combination of both RadioGraphics 2009 This is your reprint order form or pro forma invoice (Please keep a copy of this document for your records.) 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Melanocytes occur normally within the leptomeninges and are more concentrated at the base of the brain and on the ventral surface of the cervical spinal cord In these locations, pigmented leptomeninges