Clinical review Neurocutaneous melanosis: Definition and review of the literature Julie N. Kadonaga, MD,a and Ilona 1. Frieden, MDa,b San Francisco, California Neurocutaneous melanosis is a rare congenital syndrome characterized by the presence of large or multiple congenital melanocytic nevi and benign or malignant pigment cell tumors of the leptomeninges. The syndrome is thought to represent an error in the morphogenesis of the embryonal neuroectoderm. We review 39 reported cases of neurocutaneous melanosis and propose revised criteria for diagnosis. Most patients with neurocutaneous melanosis presented in the first 2years oflife with neurologic manifestations of increased intracranial pressure, mass lesions, or spinal cord compression. Leptomeningeal melanoma was presentin 62% of the cases, but even in the absence of melanoma, symptomatic neurocutaneous melanosis had an extremely poor prognosis. Useful diagnostic procedures include cerebrospinal fluid cytology and magnetic resonance imaging with gadolinium contrast. Patients may be aided by palliative measures such as shunt placement to reduce intracranial pressure. Dermatologists in their follow-up of patients with large or multiple congenital melanocytic nevi should be aware of this condition, to aid in prompt diagnosis and because the treatment of cutaneous lesions may be altered in the presence of symptomatic neurocutaneous melanosis. (J AM ACAD DERMATOL 1991;24:747-55.)
In 1861 Rokitansky1, 2 described a 14-year-old girl with a giant congenital pigmented nevus, mental retardation, and late-onset hydrocephalus. Postmortem examination revealed diffuse infiltration of the leptomeninges with benign melanin-containing cells. This case represents the first description of neurocutaneous melanosis (NCM), although the term had been initially used by van Bogaert3,4 in 1948 to describe a different clinical entity, later renamed heredofamilial melanosis. NCM is a rare congenital syndrome characterized by the development of congenital melanocytic nevi and benign or malignant melanotic tumors of the central nervous system. At least 97 cases of NCM have been reported, the vast majority in the neurosurgery literature. Dermatologists are commonly consulted because of the presence of large or multiple congenital nevi. A small but not insignificant proportion ofthese patients will have neurologic signs and symptoms because of melanosis of the nervous system. We present a review ofthe literature From the Departments ofDermatology" and Pediatrics,B,b University of Califomia School of Medicine. Reprint requests: Ilona J. Frieden, MD, Department of Dermatology, Box 0316, A·309, University of California School of Medicine, San Francisco, CA 94143.
16/1/26935
to increase the awareness among dermatologists of this lethal syndrome.
DEFINITION In 1972 Fox5 proposed the following criteria for diagnosis of NCM: (1) "unduly large or unusually numerous" pigmented nevi in association with leptomeningeal melanosis or melanoma; (2) no evidence of malignant change in any of the cutaneous lesions; and (3) no evidence of malignant melanoma in any organ apart from the meninges. These criteria provided a framework for defining NCM but presented several problems. First, as Fox acknowledged, the terms large and numerous required further definition. Large has been defined in a variety of ways.6-IO A definition currently in popular use, "equal to or larger than 20cm in diameter)" has been applied both to adults and to infants. 1l -13 Second, the presence of malignant melanoma creates problems in diagnosis. When both cutaneous and meningeal melanoma are present, the possibility of malignant metastasis, either from the skin to the meninges or from the meninges to the skin cannot be excluded. Cutaneous melanoma metastatic to the meninges is particularly important because a significant percentage of persons with "large" congenital melanocytic nevi develop cutaneous melanoma,6, 8, 9,14 and when melanoma is present,
747
Journal of the American Academy of Dermatology
748 Kadonaga and Frieden Table I. Cutaneous features of NCM Cutaneous feature
"Giant" pigmented nevi Lumbosacral region or "bathing trunk" distribution "Cape" distribution Anterior truncal distribution Numerous lesions without a single "giant" lesion Head or neck lesions (or both) Posterior midline lesions
No. of patients (% )
25/38 (66) 16/25 (64)
References
8/25 (32) 1/25 (4) 13/38 (34)
1, 4, 11, 14, 16, 24, 26, 28, 32, 34, 35, 37,40,43,44 24,25,31,36,37,40 33 1, 17,21-24,26,27, 29, 30, 38, 39,41
33/35 (94) 27/28 (96)
4,11,14,16,17,21,24-32,34-44 1,4, 11, 14, 16,24-26, 28, 31-37, 40-44
the estimated incidence of central nervous system (CNS) metastases is about 40%.5,15 Metastatic leptomeningeal melanoma has been reported rarely, but could confound the diagnosis of NCM if cutaneous metastases occurred.l 6,17 Logically, NCM could be diagnosed even if cutaneous melanoma is present as long as the meningeal lesions are histologically benign. Conversely, if meningeal melanoma is present, NCM could be diagnosed in the absence of cutaneous melanoma. Although cutaneous melanoma could regress and be undetectable in the face of CNS metastases, for practical purposes, we will assume that if the e~amined portions of the cutaneous lesions appear histologically benign, then cutaneous melanoma was not present. Primary melanoma rarely arises in an organ apart from the skin or meninges. Primary intraocular melanoma virtually never occurs in children and has not been reported in association with NCM.17,18 Thus melanoma outside of the skin and meninges should be considered metastatic and should not preclude the diagnosis of NCM. Because of these problems we believe a revision of Fox's definition ofNCM is in order and propose the following criteria for the diagnosis of NCM: 1. Large or multiple congenital nevi in association with meningeal melanosis or melanoma. Large refers to a lesion that is, or is estimated to become, equal to or greater than 20 cm in (largest) diameter in an adult. For practical purposes, this includes lesions in neonates and infants that approximate 9 em in diameter on the head or 6 cm in diameter on the body. (These values are based on neonatal and adult regional body surface areas and assume proportionate growth between the nevus and unaffected skin. 12, 19,20) Multiple is greater than or equal to three lesions (the least number of nevi reported in a patient with NCM).21
2. No evidence ofcutaneous melanoma, except in patients in whom the examined areas of the meningeal lesions are histologically benign. 3. No evidence of meningeal melanoma, except in patients in whom the examined areas of the cutaneous lesions are histologically benign. Those cases with histologic confirmation of the CNS lesions are considered definite; all others are labeled provisional. REVIEW OF CASES
We reviewed 52 patients with NCM reported in the English language literature from 1861 to 1989. The review was hampered in several cases by vague descriptions of cutaneous lesions (grossly or histopathologically),2, 17, 21-27 antiquated terminology,28,29 or lack of cutaneous histopathology. 16, 21, 22, 26, 28-31 In one case the cutaneous lesions had clinical features of congenital nevi (numerous lesions, the largest being 7 cm in diameter) although they were not described as present from birth. 30 Given these limitations, we believe that 39 cases fulfilled the modified criteria for diagnosis. * We excluded 13 cases that were previously reported as NCM but did not meet the revised criteria, such as those without cutaneous lesions 3, 37, 45-48 or meningeallesions26, 30, 49 and those with both cutaneous and CNS melanoma.50-52 All cases were confirmed at autopsy except for seven, of which five were confirmed through surgical procedures or biopsy, or both. 17, 26, 27, 29, 44 Diagnosis in two of the patients was provisional. EPIDEMIOLOGY
NCM is a congenital syndrome that can be recognized in stillbirths 2,53 (cited in Fox5) and "'References I,
2,4,
II,
14, 16, 17,21-44.
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Neurocutaneous melanosis 749
neonates,31, 35 but occasionally may not become apparent until the second decade of life. 16, 40 In the 39 cases, a family history of extensive congenital cutaneous nevi or CNS lesions was never reported (none of 15 cases); two patients with NCM had dizygotic twins without congenital skin lesion or neurologic disorders. 36 , 42 Although N CM has not been reported in identical twins, discordance of a giant congenital nevus (without CNS lesions) has occurred in identical twins. 54 Thus the syndrome occurs sporadically and with equal representation of the sexes; in the 39 cases reviewed, the female/male ratio was 19:20. Where race was indicated, there were 11 white and 3 black patients. Although some investigators have stated that NCM appears to occur more frequently in whites,5,14 there are no populationbased estimates of racial incidence to support this observation.
PATHOGENESIS NCM is postulated to represent a congenital error in morphogenesis of the embryonal neuroectoderm. The neural crest gives rise to the melanotic cells of both skin and leptomeninges, but the specific primordial cells from which the melanin-containing cells are derived have not been identified.55, 56 Cramer57 has proposed that neural crest-derived pluripotential nerve sheath precursors migrate to the skin by way of the paraspinal ganglia and peripheral nerve sheaths and ultimately give rise to terminally differentiated melanocytes. The migration and differentiation of precursor cells occur relatively early in development; melanocytes are found in fetal epidermis at 8 to 10 weeks' gestation,58 and melanotic cells have been identified in the meninges at 5.5 months' gestation. 22 Cramer's theory may also help explain many of the histologic features of congenital nevi and CNS lesions in NCM. Migration occurs along the autonomic and sensory nerves that supply the epidermis and dermis as well as vascular and adnexal structures. This may account for the extension of nevus cells into the reticular dermis, their association with adnexal structures, and also their presence in the perivascular infiltrate of both congenital nevi and CNS lesions in NCM. Happle59 has proposed that NCM, as well as a variety ofother congenital hamartomas, could result from a dominant lethal gene that survives by mosaicism. The epidemiology of NCM, with no evidence of familial inheritance, with equal numbers of males
Fig. 1. A 2Yz-month-old infant with presumptive NCM who presented with hydrocephalus. Note numerous congenital melanocytic nevi on scalp, a finding noted in 94% of cases reviewed. In the right temporal area, a ventriculoperitoneal shunt can be seen. and female persons affected, and with a patchy distribution of involvement, is consistent with the hypothesis, but more genetic studies are needed to evaluate its validity.
CUTANEOUS LESIONS IN NCM The cutaneous lesions of NCM are large and numerous congenital melanocytic nevi (Table 1). In the 39 cases, 66% of patients had "giant" pigmented lesions, whereas 34% had numerous congenital nevi without a prominent large lesion. Of 25 patients with giant nevi, 64% had lesions in a "bathing trunk" or lumbosacral distribution, 32% had the "cape" variety (occipital area, upper back), and 4% (I patient) had lesions predominatly on the anterior trunk. In one patient only,42 extensive slate-gray lesions of dermal melanocytosis were present in association with nevus flammeus (phakomatosis pigmentovascularis, lIb). In more than two thirds of patients with giant nevi, the main portion of the nevus was not overlying the scalp and neck; however, nearly all these patients had small or medium-sized congeni-
750 Kadonaga and Frieden
Journal of the American Academy of Dermatology
Fig. 2. "Giant" congenital melanocytic nevi over mid portion of back of same infant with presumptive NCM. The central linear scarlike area appeared spontaneously, without previous surgery.
tal melanocytic nevi on the scalp, face, or neck. It is unclear whether patients with lesions of the scalp, face, or, neck are actually at increased risk for leptomeningeal involvement, because many persons with these lesions do not develop NCM. It does appear, however, that patients without any nevi on the head or neck rarely develop N eM because in our series 94% had such lesions (33 of 35 cases) (Figs. 1 and 2). It also appears that persons without posterior midline lesions rarely develop NCM (reported in 1 of28 cases23 ). A1139 patients had either posterior midline nevi or head or neck lesions. In comparison, the combined data of Lorentzen et aL 6 and Gari et aL II suggest that giant nevi in general are distributed on the head and posterior midline area in 60% of patients, but that 40% are centered on the abdomen, lateral back, or extremities. The histologic features of the cutaneous lesions in NCM are the same as those found in congenital melanocytic nevi without neurologic involvement, which have been well characterized by Mark et al.60 Inthe cases reviewed, two thirds of the lesions were described as intradermal melanocytic nevi and onethird as compound nevi. In those cases in which the histopathology was described, the nevus cells extended into the reticular dermis and occasionally the subcutis; nevus cells were present between collagen bundles and around appendages, nerves, and blood vessels. * One patient had a skin biopsy specimen consistent
*Rcfcrcnces
2,13,33,34,37,41,42.
with neurofibroma in addition to specimens that demonstrated compound nevi. 37 Several authors have noted that congenital melanocytic nevi may share clinical and sometimes microscopic characteristics with neurofibromas; nevi may express neural differentiation by forming collections offibrillary collagen as well as structures resembling WagnerMeissner's corpuscles, Verocay bodies, or neuroid tubes. 14, 61, 62 In addition, giant "neuroid" nevi, like tissue in neurofibromatosis, are nonspecificcholinesterase positive.1 4 Thus the rare cases of coexistent NCM and neurofibromatosis that have been reported5 should be interpreted with caution. In addition to the histologic features mentioned, macular congenital me1anocytic nevi may appear virtually identical to cafe-au-lait spots. Ideally, confirmatory biopsy specimens of cafe-au-lait spots and documentation of Lisch nodules or other stigmata of neurofibromatosis should be obtained before coexistent neurofibromatosis and NCM are diagnosed. The use ofimmunohistochemical markers, such as factor XIII a, can help distinguish neurofibromas from neurotized nevi, and identification of genetic markers for neurofibromatosis can allow more definitive diagnosis in affected persons. 63 , 64 Although both syndromes are considered "phakomatoses," NCM is a separate and distinct clinical entity from neurofibromatosis. NEUROLOGIC MANIFESTATIONS OF NCM
Patients with NCM most frequently had neurologic manifestations within the first 2 years of life or, less frequently, in the second or third decade in life
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Neurocutaneous melanosis 751 15
Number of
10
Patients 5
o
0-11m
12-23m
2-4y
5-7y
a-loy
ll-13y
14-16y
l7-19y
20y+
Age ("m" denotes months; "y" years)
Fig. 3. Age at presentation of neurologic manifestations of NCM.
(Fig. 3). The majority of infants and young children with NCM had symptoms and signs of increased intracranial pressure, such as irritability, lethargy, headache, recurrent vomiting, generalized seizures, increased head circumference, bulging anterior fontanelle, photophobia, papilledema, neck stiffness, and, occasionally, cranial nerve palsies, particularly cranial nerves VI and VII. * With disease progression, some patients developed an ataxic gait and later in the course lost the ability to walk or to sit upright. t Bowel and bladder dysfunction occasionally developed with advanced disease. 16, 17,27,29,30,34 Developmental delay was also reported. 1,21,26,27,29,42 Patients who presented near puberty tended to have symptoms and signs of intracranial mass lesions and spinal cord compression; thus, in addition to evidence of increased intracranial pressure, these patients occasionally developed psychiatric symptoms, 14, 22,32 expressive aphasia or dysarthria ,16, 21, 22, 26, 28, 40 focal seizures,4, 2J, 2ll or 10calizing sensorimotor changes.:/: OTHER CLINICAL CONDITIONS
Other conditions reported in patients with NCM include Meckel's diverticulum,2 urinary tract anomalies, that is, renal pelvis and ureteral malformations 26 and unilateral renal cyst, I 7 and neoplasms, such as rhabdomyosarcoma. 31 ,37 Infections of the meninges 35,43 or respiratory system1,2,23,31,37,43 were frequently fatal. In addition, anorexia and general wasting were noted in seven patients. J, 21, 26, 30, 36, 37 4, 14, 16,21-30, 32, 34-42. 16,17,21,24,25,27-29,37,39,40,42,44. tRefercnces J 6, 22, 27, 34, 36, 40, 44. "References
NEUROPATHOLOGY
In NCM, "melanosis" refers to an excess of benign melanotic cells in the meninges that may be nodular or diffuse. Melanosis occurs over the convexities, base of the brain, and ventral surfaces ofthe pons, medulla, and upper cervical and lumbosacral spinal cord, areas that may have macroscopic pigmentation under normal circumstances 5, 65, 66; thus it is the extent of melanotic infiltration, not the distribution of lesions, that differentiates pathologic melanosis from physiologic pigmentation. In the 39 cases we reviewed, 97% had marked melanosis ofthe meninges, 88% with cranial involvement and 88% with spinal involvement. Melanosis was confined to the cranial leptomeninges in one patient33 and was limited to the spinal meninges in another. 26 One patient24 had macroscopically normalleptomeninges but histopathologic and clinical findings consistent with NCM. On histologic examination the melanotic cells may be pleomorphic or predominantly spindle shaped, round, oval, or polygonal; mitoses may be seen with varying frequency. 5, 27 Because the pigmented cells in the meninges have not been well characterized, Fox s suggested the general description "melanotic cells", rather than "melanocyte" or "melanoblast," which imply specific cell types. Under physiologic conditions, melanotic cells may surround blood vessels but do not extend into the Virchow-Robin spaces 24; in NCM melanotic cells form a marked perivascular infiltrate and characteristically fill the Virchow-Robin spaces. Hydrocephalus was present in 64% of cases* (23 of 36); 64% ofthese were ofthe communicating type
tReferences
"References 1,4,
17,22·27, 29,34,35,38-42.
Journal of the American Academy of Dermatology
752 Kadonaga and Frieden and were attributed to the accumulation of melanotic cells at the basal subarachnoid cisterns, with subsequent obstruction of cerebrospinal fluid (CSF) flow and prevention of CSF reabsorption in the arachnoid villi; 36% of cases were of the noncommunicating type of hydrocephalus caused by aqueductal stenosis or obstruction of outflow foramina by melanotic cells. Other findings included posterior fossa cysts or cystlike malformations, occasionally associated with melanotic tumor masses. n , 22, 26, 41 Malformations of the spinal column, such as syringomyelia, intraspinal subdural melanotic arachnoid cyst with an associated defect of the thoracic vertebra, and intraspinal lipoma, werealso reported.27, 29,44Rarely vascular anomalies of the eNS were described: one patient had multiple pial telangiectases over the medial aspect of the left cerebral hemisphere35; another had coexistent encephalotrigeminal angiomatosis (Sturge-Weber syndrome) and NCM.42 Intracranial and subarachnoid hemorrhages were also reported.4, 21, 35, 37, 40 Leptomeningeal melanoma was diagnosed in 62% of cases (14 of 27). Half of the patients had an intracranial tumor at autopsy, most frequently in the frontal and temporal lobes. * In two patients extracranial melanoma was also present and was thought to represent metastasis from meningeal melanoma; lesions, were discovered in the orbit, liver, ribs, and lumbar vertebrae. 16, 17 In four patients metastatic lesions occurred in association with a ventriculoperitoneal or lumboperitoneal shunt, with melanotic tumors in the peritoneum, omentum, abdominal lymph nodes, liver, and pleura. 11, 25, 26, 40 Fourteen patients with shunts over an average of 12 months (up to 5 years) had no evidence of metastases associated with the shunt. t Melanoma has probably been overdiagnosed in patients with NCM; differentiation of benign from malignant lesions is difficult because of the marked cellular pleomorphism and the occurrence of cells in nests or nodules, as well as the appearance of parenchymal invasion resulting from the melanotic infiltration of the V~rchow-Robin spaces and the presence of melanophores (melanin-laden histiocytes that may cause macroscopic pigmentation of the eNS parenchyma). Yu et a1. 41 have described features that aid in the differentiation of meningeal "References
4, 14, 16,21,24,30,32,36,40,41,43.
tReferences
17,23,24,26,27,29,37-42.
melanosis from melanoma: (1) benign tumor collections lack necrosis and hemorrhage; (2) pigment cells may surround blood vessel walls but do not invade the basal lamina; (3) melanotic cells lack cellular atypia and frequent mitotic activity; and (4) pigment cells lack annulate lamellae (concentric lamellar structures thought to represent modified melanosomes. 67 Unfortunately the distinction is not necessarily a clinically significant one, because symptomatic NCM almost universally carries a poor prognosis regardless of the presence of absence of malignancy. In those patients with melanoma treated with radiation or chemotherapy, treatment had little effect on symptoms and the rapid course of this lethal syndrome.
LABORATORY EVALUATION CSF pressure in NCM was frequently elevated; when described, CSF typically had elevated protein and normal glucose levels and a sterile leukocytosis. Seven of 11 patients had elevated CSF red blood cell counts* and five had xanthochromic fluid 21 ,22, 25,34,35; in some patients melanin granules rather than hemosiderin or elevated protein levels may have caused the yellow discoloration of fluid. 22 CSF cytology revealed malignant cells in only two of five patients 25 ,32 numerous "melanin~containing cells" were observed in one patient,29 and free melanin granules were found in two of three patients. 16,36 Electroencephalographic studies frequently demonstrated either focal or generalized abnormalities. Hydrocephalus and mass lesions were identified with various imaging procedures. With tumors involving the meninges, computed tomography with contrast most commonly shows enhancement of the leptomeninges overlying the brain stem and basilar cisterns,68 and this has been described in meningeal melanosis. 39 Magnetic resonance imaging with gadolinium contrast (MRI-Gd) has been found to be more sensitive than computed tomography and noncontrast MRI in screening certain intracerebral lesions, and it is the diagnostic procedure of choice in the evaluation of hydrocephalus. 69-71 MRI-Gd has also been useful in the evaluation of extracerebral tumors, such as intraventricular and meningeal tumors, and may detect early meningeal thickening.29, 71, 72
"References
21, 26, 35, 36,40,41,43.
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Neurocutaneous melanosis 753
TREATMENT AND PROGNOSIS
RECOMMENDATIONS
Rarely NCM may be asymptomatic and discovered incidentally at postmortem examination37,65; the long-term prognosis for these patients is unknown. All other patients described in the literature had neurologic symptoms, and in the vast majority the clinical course was characterized by progressive deterioration and early death. Only 8% (3 of 39) of the patients were living when their cases were reported. 26 ,27, 44 Of the 36 who died, 70% died before 10 years of age; only 4 lived beyond the age of 25. 16, 30,32,40 The interval between the patient's age at initial presentation with NCM and death ranged from immediate2 to 21 years 42 ; more than half (19 of 35; 54%) of the fatalities occurred within 3 years of their initial presentation with neurologic manifestations. Unfortunately antineoplastic therapy has not significantly ameliorated symptoms and has not altered the rapid course of NCM; all seven patients who received radiation or chemotherapy died within the first year of treatment. * In general, patients who were treated with palliative surgical measures, such as shunt placement to reduce intracranial pressure, improved at least transiently.24-27,39 No case reports described extensive cutaneous surgery for reduction of skin lesions in patients known to have NCM; in three patients excisional operations had been performed in the first 2 years of life without complications24,25, 40; in one patient NCM was "unmasked," with the development of seizures during premedication in preparation for surgery.40 Even in the absence of N CM, the role of extensive surgical procedures in giant congenital melanocytic nevi excision is controversial. Most authors6,8-10, 12, 14, 73 advocate surgery to reduce the risk of melanoma estimated to occur in a significant number of patients (approximately 5% to 15%).9,74 In addition, surgery may improve the cosmetic appearance of affected patients. An estimated 40% to 62% of patients with NCM will develop leptomeningeal melanoma, 5 and even in the presence of benign CNS lesions the condition is usually clinically malignant. When the poor prognosis, the risks of general anesthesia,75 and the physical and psychological trauma of surgery76 are considered, prophylactic cutaneous surgery is probably rarely, if ever, indicated in symptomatic cases of NCM..
Dermatologists, in their follow-up of patients with large or numerous congenital melanocytic nevi, are in a position to detect the development of neurologic involvement early in the course and may have an impact on the quality of life for these patients. Most patients are seen in early infancy; they should be seen relatively frequently, as dictated by the appearance of, and approach to, the cutaneous lesions. Open communication between the dermatologist and the pediatrician could facilitate early detection of neurologic manifestations. Physicians should be watchful for signs and symptoms of increased intracranial pressure. which include lethargy, irritability, headache, recurrent vomiting, seizures, and photophobia, and should also look for evidence of developmental delay. Head circumference should be measured regularly because disproportionate increase could be an early sign ofhydrocephalus. The second peak age of presentation with neurologic manifestations occurs in the second and third decades of life, when patients tend to present with the signs and symptoms of intracranial mass lesions and spinal cord compression, as well as increased intracranial pressure. The yield and cost-effectiveness of CNS evaluation by CSF cytology and MRI-Gd scanning are uncertain because the incidence of CNS involvement in the population at risk is not known, and no specific recommendations can be made regarding indications for CNS evaluation before excisional skin surgery. Our review suggests that patients with large or multiple nevi on the head, neck, or posterior midline may have an increased risk of leptomeningeal melanosis detectable by MRI-Gd. This would be a fruitful area for further investigation.
*References
16,23,25,31,32,34,40.
REFERENCES
1. Rokitansky J. Ein ausgezeichneter Fall von Pigment-Mal mit ausgebreiteter Pigmentierung der inneren Him- und Riichenmarkshaute. Allg Wien Moo Z 1861 ;6:1 13-6. 2. MacLachlan WWG. Extensive pigmentation of the brain associated with nevi pigmentosi of the skin. J Med Res 1913;29:433-47. 3. Van Bogaert L. La melanose neurocutanee diffuse heredofamiliale. Bull Acad R Med Belg 1948;13:397-428. 4. Lamas E, Lobato RD, Sotelo T, et al. Neurocutaneous melanosis: report of a case and review ofthe literature. Acta Neurochir (Wien) 1977;36:93-105. 5. Fox H. Neurocutaneous melanosis. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology. Amsterdam: North Holland, 1972:414-28; vol 14. 6. Lorentzen M, Pers M, Bretteville-Jensen G. The incidence of malignant transformation in giant pigmented nevi. Scand J Plast Reconstr Surg 1977;I 1:163-7.
Journal of the American Academy of Dermatology
754 Kadonaga and Frieden 7. Quaba AA, WalJace AF. The incidence of malignant melanoma (0 to 15 years of age) arising in "large" congenital nevocellular nevi. Plast Reconstr Surg 1986;78:174-9. 8. Greeley PW, Middleton AG, Curtin JW. Incidence of malignancy in giant pigmented nevi. Plast Reconstr Surg 1965;36:26-37. 9. Rhodes AR, Wood WC, Sober AJ, et al. Nonepidermal origin of malignant melanoma with giant congenital nevacellular nevus. Plast Reconstr Surg 1981;67:782-90. 10. Pilney FA, Broadbent TR, Woolf RM. Giant pigmented nevi of the face: surgical management. Plast Reconstr Surg 1967;40:469-74. 11. Gari LM, Rivers JK, Kopf AW. Melanomas arising in large congenital nevocytic nevi: a prospective study. Pediatr DermatoI1988;5:151-8. 12. Kopf A W, Bart RS, Hennessey P. Congenital nevocytic nevi and malignant melanomas. J AM ACAD DERMATOL 1980;1:123-30. 13. National Institutes of Health Consensus Development Conference statement, Oct. 24-26, 1983. Precursors to malignant melanoma. J AM ACAD DERMATOL 1984;10: 683-8. 14. Reed WB, Becker SW Sr, Becker SW Jr, et al. Giant pigmented nevi, melanoma, and leptomeningeal melanocytasis. Arch Dermatol 1965;91:100-19. 15. Das Gupta T, Brasfield R. Metastatic melanoma: a clinicopathological study. Cancer 1964;17:1323-39. 16. Kaplan AM, Itabashi HH, Hanelin LG, et al. Neurocutaneous melanosis with malignant leptomeningeal melanoma. Arch Neural 1975;32:669-71. 17. Ellis DS, Spencer WH, Stephenson CM. Congenital neurocutaneous melanosis with metastatic orbital malignant melanoma. Ophthalmology 1986;93:1639-42. 18. Jakobiec FA, Ellsworth R, Tannenbaum M. Primary orbital melanoma. Am J Ophtha1molI974;78:24-39. 19. Guy RH, Maibach HI. Calculations ofbody exposure from percutaneous absorption data. In: Bronough RL, Maibach HI, eds. Percutaneous absorption: mechanisms, methodology, drug delivery. New York: Marcel Dekker, 1985: 461-6. 20. Kadonaga IN, Frieden IL. Unpublished observations. 21. Fischer S. Primary perivascular cerebral, cerebellar, and leptomeningeal melanoma. Acta Psychiatr Scand 1956; 31:21-34. 22. Farnell JF, Globus JH. Primary melanoblastosis oftheleptomeninges and brain. Arch N eurolPsychiatr 1931; 25:80323. 23. Williams HI. Primary malignant meningeal melanoma associated with benign hairy nevi. J Pathol Bacterial 1969; 99:171-4. 24. Fox H, Emery JL. Goodbody RA, et al. Neurocutaneous melanosis. Arch Dis Child 1964;39:508-16. 25. Hoffman HJ, Freeman A. Primary malignant leptomeningeal melanoma in association with giant hariy nevi: report of two cases. J Neurosurg 1967;26:62-71. 26. Humes RA, Roskamp J, Eisenbrey AB. Melanosis and hydrocephalus: report of four cases. J Neurosurg 1984;61: 365-8. 27. Leaney BJ, Rowe PW, Klug GL. Neurocutaneous melanosis with hydrocephalus and syringomyelia. J N eurosurg 1985;62:148-52. 28. Tveton L. Primary meningeal melanosis. Acta Pathol Microbiol Scand 1965;63:1-10. 29. Van Heuzen EP, Kaiser CM, de Slegte RGM. N eurocuta-
30. 31.
32. 33. 34. 35. 36. 37. 38. 39. 40. 41.
42. 43. 44. 45. 46. 47. 48. 49. 50. 51.
neous melanosis associated with intraspinal lipoma. Neuroradiology 1989;31:349-51. Christensen E. Two cases of primary intracranial melanoma. Acta Chir Scand 1941;85:90-8. Zuniga A, Las Heras J, Benveniste S. Rhabdomyosarcoma arising in a congenital giant nevus associated with neurocutaneous melanosis in a neonate. J Pediatr Surg 1987; 22:1036-8. Thomas CS, Toone BK, Rose PE. Neurocutaneous melanosis and psychosis [Letter]. Am J Psychiatry 1988; 145:649-50. Grahl F. Angeborener ausgedehnter Naevus pigmentosus in Verbindung mit Pigment-Flecken im Gehirn. Beitr z path. Anat u z aUg Path 1906;39:66-81. Netherton EW. Extensive pigmented nevus associated with primary melanoblastosis of leptomeninges of brain and cord. Arch Dermatol Syph 1936;33:238-58. Wilcox JC. Melanomatosis of the skin and central nervous sytem in infants.Am J Dis Child 1939;57:391-400. Morris LL, Danta G. Malignant cerebral melanoma complicating giant pigmented naevus: a case report. J Neurol Neurasurg Psychiatry 1968;31 :628-32. Slaughter JC, Hardman JM, Kempe LG, et al. Neurocutaneous melanosis and leptomeningeal melanomatosis in children. Arch Pathol 1969;88:298-304. Harper CG, Thomas DGT. Neurocutaneous melanosis. J Neural Neurosurg Psychiatry 1974;37:760-3. Kudel TA, Bingham WT, Tubman DE. CT findings of primary malignant leptomeningeal melanoma in neurocutaneous melanosis. Am J RadioI1979;133:950-1. Faillace WJ, Okawara S, McDonald JV. NCM with extensive intracerebral and spinal involvement: report of two cases. J Neurosurg 1984;61:782-5. Yu H, Tsaur K, Chein C, et at. Neurocutaneous melanosis: electron microscopic comparison of the pigmented melanocytic nevi of skin and meningeal melanosis. J Dermatol (Tokyo) 1985;12:267-76. Novotny El, Urich H. The coincidence of neurocutaneous melanosis and encephalofacial angiomatosis. Clin NeuropathoI1986;5:246-51. Adeyanju M, Reyes MG, Junaid AT. Fatal pneumococcal infection in neurocutaneous melanosis [Letter]. J Child NeuroI1988;3:293-4. Kasantikul V, Shuangshoti S, Pattanaruenglai A, et al. Intraspinal melanotic arachnoid cyst and lipoma in NCM. Surg Neurol 1989;31:138-41. Kessler MM. Melanoblastosis and melanoblastoma: primary and secondary involvement of the brain. Am J Cancer 1937;30:19-31. Schnitker MT, Ayer D. The primary melanomas of the leptomeninges. J Nerv Ment Dis 1938;87:45-73. Bouton J. Primary melanoma of the leptomeninges. J Clin PathoI1958;11:122-7. Gilmor RL, Mealey JM Jr. Melanotic neuroectodermal tumor involving the cranium in infancy. J Neurosurg 1972;36:507-11. Leno C, Sedano MJ, Combarros 0, et al. Congenital giant pigment nevus and intracranial arteriovenous malformation. Surg NeuroI1989;31:407-8. Narayanan HS, Gandhi DH, Girimaji SR. Neurocutane-, ous melanosis associated with Dandy-Walker syndrome. Clin Neurol Neurosurg 1987;89:197-200. Schultz RC. Fatal malignant melanoma in children with giant nevi. Plast Reconstr Surg 1961;27:551-7.
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52. Schneiderman H, Wu Ay, Campbell W A, et a1. Congenital melanoma with multiple prenatal metastases. Cancer 1987;60:1371-7. 53. Binsack A. Ein fall von angeborene ausgedehnte Naevus pigmentosus mit Pigment-Flecken im Gehirn [Thesis]. Giessen: 1972. 54. Amir J, Metzker A, Nitzan M. Giant pigmented nevus occurring in one identical twin. Arch Dermatol 1982;118: 188-9. 55. Newth DR. A remarkable embryonic tissue. Br Med J 1951;3:96-9. 56. Rawles ME. Origin of melanophores and their role in development of color patterns in vertebrates. Physiol Rev 1948;28:383-408. 57. Cramer SF. The me1anocytic differentiation pathway in congenital melanocytic nevi: theoretical considerations. Pediatr PathoI1988;8:253-65. 58. Sagebiel RW, Odland GF. Ultrastructural identification of melanocytes in early human embryos. In: Proceedings of the VIIth International Pigment Cell Conference. New York: Appleton & Lange, 1972:43-50. 59. Happle R. Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin. J AM ACAD DERMATOL 1987;16:899-906. 60. Mark GJ, Mihm MC, Liteplo MG, et aJ. Congenital melanocytic nevi of the small and garment type: clinical, histologic and ultrastructural studies. Hum PathoI1973;4:395418. 61. Solomon L, Eng AM, Bene M, et a1. Giant congenital neuroid melanocytic nevus. Arch DermatoI1980;ll6:318-20. 62. Maize JC, Ackerman AB. Pigmented lesions of the skin: Clinicopathologic correlations. Philadelphia: Lea & Febiger, 1987:73-130. 63. Gray MH, Smoller BR, McNutt S, et aJ. Immunohistochemical demonstration of factor XlIIa expression in neurofibromas. Arch DermatoI1990;126:472-6.
Neurocutaneous melanosis 755 64. National Institutes of Health Consensus Development Conference statement. Neurofibromatosis. Arch Neurol 1988;45:575-8. 65. Pascual-Castroviejo 1. Neurocutaneous melanosis, In: Gomez M, ed. Neurocutaneous diseases. Boston: Butterworth, 1987:329-34. 66. Savitz MH, Anderson PJ. Primary melanoma of the leptomeninges: a review. Mt Sinai J Med 1974;41:774-9l. 67. O'Valle F, Aneiros J, Osuna A, et a1. Human melanoma cell lines: an immunofluorescence and ultrastructural study. J Cutan PathoI1988;lS:374-9. 68. Enzman DR, Krikorian J, Yorke C, et aJ. Computed tomography in leptomeningeal spread of tumor. J Comput Assist Tomogr 1978;128:57-63. 69. Valk J, de Slegte D M, Crezee FC, et aJ. Contrast enhanced MRI of the brain using gadolinium-DPTA. Acta Radiol 1987;28:659-65. 70. Britton J, March H, Kendall B, et a1. MRI and hydrocephalus in childhood. Neuroradiology 1988;30:310-4. 71. Cohen BH, Bury E, Packer RJ, et a1. Gadolinium-DPTAenhanced magnetic resonance imaging in childhood brain tumors. Neurology 1989;39:1178-83. 72. Valk J. Gd-DPTA in MR of spinal lesions. Am J Radial 1988; ISO: 1163-8. 73. Arons MS, Hurwitz S. Congenital nevocellular nevus; a review of the treatment controversy and a report of 46 cases. Plast Reconstr Surg 1983;72:355-63. 74. Conway H. Bathing trunk nevus. Surgery 1939;6:585-97. 75. Salem MR, Bennett EF, Schweiss JF, et aI. Cardiac arrest related to anesthesia: contributing factors in infants and children. JAMA 1975;233:238-41. 76. Backman ME, Kopf AW. Iatrogenic effects of general anesthesia in children: considerations in treating large congenital nevocytic nevi. J Dermatol Surg Oncol 1986;12: 363-7.
In 1861 Rokitansky1, 2 described a 14-year-old girl with a giant congenital pigmented nevus, mental retardation, and late-onset hydrocephalus. Postmortem examination revealed diffuse infiltration of the leptomeninges with benign melanin-containing cells. This case represents the first description of neurocutaneous melanosis (NCM), although the term had been initially used by van Bogaert3,4 in 1948 to describe a different clinical entity, later renamed heredofamilial melanosis. NCM is a rare congenital syndrome characterized by the development of congenital melanocytic nevi and benign or malignant melanotic tumors of the central nervous system. At least 97 cases of NCM have been reported, the vast majority in the neurosurgery literature. Dermatologists are commonly consulted because of the presence of large or multiple congenital nevi. A small but not insignificant proportion ofthese patients will have neurologic signs and symptoms because of melanosis of the nervous system. We present a review ofthe literature From the Departments ofDermatology" and Pediatrics,B,b University of Califomia School of Medicine. Reprint requests: Ilona J. Frieden, MD, Department of Dermatology, Box 0316, A·309, University of California School of Medicine, San Francisco, CA 94143.
16/1/26935
to increase the awareness among dermatologists of this lethal syndrome.
DEFINITION In 1972 Fox5 proposed the following criteria for diagnosis of NCM: (1) "unduly large or unusually numerous" pigmented nevi in association with leptomeningeal melanosis or melanoma; (2) no evidence of malignant change in any of the cutaneous lesions; and (3) no evidence of malignant melanoma in any organ apart from the meninges. These criteria provided a framework for defining NCM but presented several problems. First, as Fox acknowledged, the terms large and numerous required further definition. Large has been defined in a variety of ways.6-IO A definition currently in popular use, "equal to or larger than 20cm in diameter)" has been applied both to adults and to infants. 1l -13 Second, the presence of malignant melanoma creates problems in diagnosis. When both cutaneous and meningeal melanoma are present, the possibility of malignant metastasis, either from the skin to the meninges or from the meninges to the skin cannot be excluded. Cutaneous melanoma metastatic to the meninges is particularly important because a significant percentage of persons with "large" congenital melanocytic nevi develop cutaneous melanoma,6, 8, 9,14 and when melanoma is present,
747
Journal of the American Academy of Dermatology
748 Kadonaga and Frieden Table I. Cutaneous features of NCM Cutaneous feature
"Giant" pigmented nevi Lumbosacral region or "bathing trunk" distribution "Cape" distribution Anterior truncal distribution Numerous lesions without a single "giant" lesion Head or neck lesions (or both) Posterior midline lesions
No. of patients (% )
25/38 (66) 16/25 (64)
References
8/25 (32) 1/25 (4) 13/38 (34)
1, 4, 11, 14, 16, 24, 26, 28, 32, 34, 35, 37,40,43,44 24,25,31,36,37,40 33 1, 17,21-24,26,27, 29, 30, 38, 39,41
33/35 (94) 27/28 (96)
4,11,14,16,17,21,24-32,34-44 1,4, 11, 14, 16,24-26, 28, 31-37, 40-44
the estimated incidence of central nervous system (CNS) metastases is about 40%.5,15 Metastatic leptomeningeal melanoma has been reported rarely, but could confound the diagnosis of NCM if cutaneous metastases occurred.l 6,17 Logically, NCM could be diagnosed even if cutaneous melanoma is present as long as the meningeal lesions are histologically benign. Conversely, if meningeal melanoma is present, NCM could be diagnosed in the absence of cutaneous melanoma. Although cutaneous melanoma could regress and be undetectable in the face of CNS metastases, for practical purposes, we will assume that if the e~amined portions of the cutaneous lesions appear histologically benign, then cutaneous melanoma was not present. Primary melanoma rarely arises in an organ apart from the skin or meninges. Primary intraocular melanoma virtually never occurs in children and has not been reported in association with NCM.17,18 Thus melanoma outside of the skin and meninges should be considered metastatic and should not preclude the diagnosis of NCM. Because of these problems we believe a revision of Fox's definition ofNCM is in order and propose the following criteria for the diagnosis of NCM: 1. Large or multiple congenital nevi in association with meningeal melanosis or melanoma. Large refers to a lesion that is, or is estimated to become, equal to or greater than 20 cm in (largest) diameter in an adult. For practical purposes, this includes lesions in neonates and infants that approximate 9 em in diameter on the head or 6 cm in diameter on the body. (These values are based on neonatal and adult regional body surface areas and assume proportionate growth between the nevus and unaffected skin. 12, 19,20) Multiple is greater than or equal to three lesions (the least number of nevi reported in a patient with NCM).21
2. No evidence ofcutaneous melanoma, except in patients in whom the examined areas of the meningeal lesions are histologically benign. 3. No evidence of meningeal melanoma, except in patients in whom the examined areas of the cutaneous lesions are histologically benign. Those cases with histologic confirmation of the CNS lesions are considered definite; all others are labeled provisional. REVIEW OF CASES
We reviewed 52 patients with NCM reported in the English language literature from 1861 to 1989. The review was hampered in several cases by vague descriptions of cutaneous lesions (grossly or histopathologically),2, 17, 21-27 antiquated terminology,28,29 or lack of cutaneous histopathology. 16, 21, 22, 26, 28-31 In one case the cutaneous lesions had clinical features of congenital nevi (numerous lesions, the largest being 7 cm in diameter) although they were not described as present from birth. 30 Given these limitations, we believe that 39 cases fulfilled the modified criteria for diagnosis. * We excluded 13 cases that were previously reported as NCM but did not meet the revised criteria, such as those without cutaneous lesions 3, 37, 45-48 or meningeallesions26, 30, 49 and those with both cutaneous and CNS melanoma.50-52 All cases were confirmed at autopsy except for seven, of which five were confirmed through surgical procedures or biopsy, or both. 17, 26, 27, 29, 44 Diagnosis in two of the patients was provisional. EPIDEMIOLOGY
NCM is a congenital syndrome that can be recognized in stillbirths 2,53 (cited in Fox5) and "'References I,
2,4,
II,
14, 16, 17,21-44.
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Neurocutaneous melanosis 749
neonates,31, 35 but occasionally may not become apparent until the second decade of life. 16, 40 In the 39 cases, a family history of extensive congenital cutaneous nevi or CNS lesions was never reported (none of 15 cases); two patients with NCM had dizygotic twins without congenital skin lesion or neurologic disorders. 36 , 42 Although N CM has not been reported in identical twins, discordance of a giant congenital nevus (without CNS lesions) has occurred in identical twins. 54 Thus the syndrome occurs sporadically and with equal representation of the sexes; in the 39 cases reviewed, the female/male ratio was 19:20. Where race was indicated, there were 11 white and 3 black patients. Although some investigators have stated that NCM appears to occur more frequently in whites,5,14 there are no populationbased estimates of racial incidence to support this observation.
PATHOGENESIS NCM is postulated to represent a congenital error in morphogenesis of the embryonal neuroectoderm. The neural crest gives rise to the melanotic cells of both skin and leptomeninges, but the specific primordial cells from which the melanin-containing cells are derived have not been identified.55, 56 Cramer57 has proposed that neural crest-derived pluripotential nerve sheath precursors migrate to the skin by way of the paraspinal ganglia and peripheral nerve sheaths and ultimately give rise to terminally differentiated melanocytes. The migration and differentiation of precursor cells occur relatively early in development; melanocytes are found in fetal epidermis at 8 to 10 weeks' gestation,58 and melanotic cells have been identified in the meninges at 5.5 months' gestation. 22 Cramer's theory may also help explain many of the histologic features of congenital nevi and CNS lesions in NCM. Migration occurs along the autonomic and sensory nerves that supply the epidermis and dermis as well as vascular and adnexal structures. This may account for the extension of nevus cells into the reticular dermis, their association with adnexal structures, and also their presence in the perivascular infiltrate of both congenital nevi and CNS lesions in NCM. Happle59 has proposed that NCM, as well as a variety ofother congenital hamartomas, could result from a dominant lethal gene that survives by mosaicism. The epidemiology of NCM, with no evidence of familial inheritance, with equal numbers of males
Fig. 1. A 2Yz-month-old infant with presumptive NCM who presented with hydrocephalus. Note numerous congenital melanocytic nevi on scalp, a finding noted in 94% of cases reviewed. In the right temporal area, a ventriculoperitoneal shunt can be seen. and female persons affected, and with a patchy distribution of involvement, is consistent with the hypothesis, but more genetic studies are needed to evaluate its validity.
CUTANEOUS LESIONS IN NCM The cutaneous lesions of NCM are large and numerous congenital melanocytic nevi (Table 1). In the 39 cases, 66% of patients had "giant" pigmented lesions, whereas 34% had numerous congenital nevi without a prominent large lesion. Of 25 patients with giant nevi, 64% had lesions in a "bathing trunk" or lumbosacral distribution, 32% had the "cape" variety (occipital area, upper back), and 4% (I patient) had lesions predominatly on the anterior trunk. In one patient only,42 extensive slate-gray lesions of dermal melanocytosis were present in association with nevus flammeus (phakomatosis pigmentovascularis, lIb). In more than two thirds of patients with giant nevi, the main portion of the nevus was not overlying the scalp and neck; however, nearly all these patients had small or medium-sized congeni-
750 Kadonaga and Frieden
Journal of the American Academy of Dermatology
Fig. 2. "Giant" congenital melanocytic nevi over mid portion of back of same infant with presumptive NCM. The central linear scarlike area appeared spontaneously, without previous surgery.
tal melanocytic nevi on the scalp, face, or neck. It is unclear whether patients with lesions of the scalp, face, or, neck are actually at increased risk for leptomeningeal involvement, because many persons with these lesions do not develop NCM. It does appear, however, that patients without any nevi on the head or neck rarely develop N eM because in our series 94% had such lesions (33 of 35 cases) (Figs. 1 and 2). It also appears that persons without posterior midline lesions rarely develop NCM (reported in 1 of28 cases23 ). A1139 patients had either posterior midline nevi or head or neck lesions. In comparison, the combined data of Lorentzen et aL 6 and Gari et aL II suggest that giant nevi in general are distributed on the head and posterior midline area in 60% of patients, but that 40% are centered on the abdomen, lateral back, or extremities. The histologic features of the cutaneous lesions in NCM are the same as those found in congenital melanocytic nevi without neurologic involvement, which have been well characterized by Mark et al.60 Inthe cases reviewed, two thirds of the lesions were described as intradermal melanocytic nevi and onethird as compound nevi. In those cases in which the histopathology was described, the nevus cells extended into the reticular dermis and occasionally the subcutis; nevus cells were present between collagen bundles and around appendages, nerves, and blood vessels. * One patient had a skin biopsy specimen consistent
*Rcfcrcnces
2,13,33,34,37,41,42.
with neurofibroma in addition to specimens that demonstrated compound nevi. 37 Several authors have noted that congenital melanocytic nevi may share clinical and sometimes microscopic characteristics with neurofibromas; nevi may express neural differentiation by forming collections offibrillary collagen as well as structures resembling WagnerMeissner's corpuscles, Verocay bodies, or neuroid tubes. 14, 61, 62 In addition, giant "neuroid" nevi, like tissue in neurofibromatosis, are nonspecificcholinesterase positive.1 4 Thus the rare cases of coexistent NCM and neurofibromatosis that have been reported5 should be interpreted with caution. In addition to the histologic features mentioned, macular congenital me1anocytic nevi may appear virtually identical to cafe-au-lait spots. Ideally, confirmatory biopsy specimens of cafe-au-lait spots and documentation of Lisch nodules or other stigmata of neurofibromatosis should be obtained before coexistent neurofibromatosis and NCM are diagnosed. The use ofimmunohistochemical markers, such as factor XIII a, can help distinguish neurofibromas from neurotized nevi, and identification of genetic markers for neurofibromatosis can allow more definitive diagnosis in affected persons. 63 , 64 Although both syndromes are considered "phakomatoses," NCM is a separate and distinct clinical entity from neurofibromatosis. NEUROLOGIC MANIFESTATIONS OF NCM
Patients with NCM most frequently had neurologic manifestations within the first 2 years of life or, less frequently, in the second or third decade in life
Volume 24 Number 5, Part 1 May 1991
Neurocutaneous melanosis 751 15
Number of
10
Patients 5
o
0-11m
12-23m
2-4y
5-7y
a-loy
ll-13y
14-16y
l7-19y
20y+
Age ("m" denotes months; "y" years)
Fig. 3. Age at presentation of neurologic manifestations of NCM.
(Fig. 3). The majority of infants and young children with NCM had symptoms and signs of increased intracranial pressure, such as irritability, lethargy, headache, recurrent vomiting, generalized seizures, increased head circumference, bulging anterior fontanelle, photophobia, papilledema, neck stiffness, and, occasionally, cranial nerve palsies, particularly cranial nerves VI and VII. * With disease progression, some patients developed an ataxic gait and later in the course lost the ability to walk or to sit upright. t Bowel and bladder dysfunction occasionally developed with advanced disease. 16, 17,27,29,30,34 Developmental delay was also reported. 1,21,26,27,29,42 Patients who presented near puberty tended to have symptoms and signs of intracranial mass lesions and spinal cord compression; thus, in addition to evidence of increased intracranial pressure, these patients occasionally developed psychiatric symptoms, 14, 22,32 expressive aphasia or dysarthria ,16, 21, 22, 26, 28, 40 focal seizures,4, 2J, 2ll or 10calizing sensorimotor changes.:/: OTHER CLINICAL CONDITIONS
Other conditions reported in patients with NCM include Meckel's diverticulum,2 urinary tract anomalies, that is, renal pelvis and ureteral malformations 26 and unilateral renal cyst, I 7 and neoplasms, such as rhabdomyosarcoma. 31 ,37 Infections of the meninges 35,43 or respiratory system1,2,23,31,37,43 were frequently fatal. In addition, anorexia and general wasting were noted in seven patients. J, 21, 26, 30, 36, 37 4, 14, 16,21-30, 32, 34-42. 16,17,21,24,25,27-29,37,39,40,42,44. tRefercnces J 6, 22, 27, 34, 36, 40, 44. "References
NEUROPATHOLOGY
In NCM, "melanosis" refers to an excess of benign melanotic cells in the meninges that may be nodular or diffuse. Melanosis occurs over the convexities, base of the brain, and ventral surfaces ofthe pons, medulla, and upper cervical and lumbosacral spinal cord, areas that may have macroscopic pigmentation under normal circumstances 5, 65, 66; thus it is the extent of melanotic infiltration, not the distribution of lesions, that differentiates pathologic melanosis from physiologic pigmentation. In the 39 cases we reviewed, 97% had marked melanosis ofthe meninges, 88% with cranial involvement and 88% with spinal involvement. Melanosis was confined to the cranial leptomeninges in one patient33 and was limited to the spinal meninges in another. 26 One patient24 had macroscopically normalleptomeninges but histopathologic and clinical findings consistent with NCM. On histologic examination the melanotic cells may be pleomorphic or predominantly spindle shaped, round, oval, or polygonal; mitoses may be seen with varying frequency. 5, 27 Because the pigmented cells in the meninges have not been well characterized, Fox s suggested the general description "melanotic cells", rather than "melanocyte" or "melanoblast," which imply specific cell types. Under physiologic conditions, melanotic cells may surround blood vessels but do not extend into the Virchow-Robin spaces 24; in NCM melanotic cells form a marked perivascular infiltrate and characteristically fill the Virchow-Robin spaces. Hydrocephalus was present in 64% of cases* (23 of 36); 64% ofthese were ofthe communicating type
tReferences
"References 1,4,
17,22·27, 29,34,35,38-42.
Journal of the American Academy of Dermatology
752 Kadonaga and Frieden and were attributed to the accumulation of melanotic cells at the basal subarachnoid cisterns, with subsequent obstruction of cerebrospinal fluid (CSF) flow and prevention of CSF reabsorption in the arachnoid villi; 36% of cases were of the noncommunicating type of hydrocephalus caused by aqueductal stenosis or obstruction of outflow foramina by melanotic cells. Other findings included posterior fossa cysts or cystlike malformations, occasionally associated with melanotic tumor masses. n , 22, 26, 41 Malformations of the spinal column, such as syringomyelia, intraspinal subdural melanotic arachnoid cyst with an associated defect of the thoracic vertebra, and intraspinal lipoma, werealso reported.27, 29,44Rarely vascular anomalies of the eNS were described: one patient had multiple pial telangiectases over the medial aspect of the left cerebral hemisphere35; another had coexistent encephalotrigeminal angiomatosis (Sturge-Weber syndrome) and NCM.42 Intracranial and subarachnoid hemorrhages were also reported.4, 21, 35, 37, 40 Leptomeningeal melanoma was diagnosed in 62% of cases (14 of 27). Half of the patients had an intracranial tumor at autopsy, most frequently in the frontal and temporal lobes. * In two patients extracranial melanoma was also present and was thought to represent metastasis from meningeal melanoma; lesions, were discovered in the orbit, liver, ribs, and lumbar vertebrae. 16, 17 In four patients metastatic lesions occurred in association with a ventriculoperitoneal or lumboperitoneal shunt, with melanotic tumors in the peritoneum, omentum, abdominal lymph nodes, liver, and pleura. 11, 25, 26, 40 Fourteen patients with shunts over an average of 12 months (up to 5 years) had no evidence of metastases associated with the shunt. t Melanoma has probably been overdiagnosed in patients with NCM; differentiation of benign from malignant lesions is difficult because of the marked cellular pleomorphism and the occurrence of cells in nests or nodules, as well as the appearance of parenchymal invasion resulting from the melanotic infiltration of the V~rchow-Robin spaces and the presence of melanophores (melanin-laden histiocytes that may cause macroscopic pigmentation of the eNS parenchyma). Yu et a1. 41 have described features that aid in the differentiation of meningeal "References
4, 14, 16,21,24,30,32,36,40,41,43.
tReferences
17,23,24,26,27,29,37-42.
melanosis from melanoma: (1) benign tumor collections lack necrosis and hemorrhage; (2) pigment cells may surround blood vessel walls but do not invade the basal lamina; (3) melanotic cells lack cellular atypia and frequent mitotic activity; and (4) pigment cells lack annulate lamellae (concentric lamellar structures thought to represent modified melanosomes. 67 Unfortunately the distinction is not necessarily a clinically significant one, because symptomatic NCM almost universally carries a poor prognosis regardless of the presence of absence of malignancy. In those patients with melanoma treated with radiation or chemotherapy, treatment had little effect on symptoms and the rapid course of this lethal syndrome.
LABORATORY EVALUATION CSF pressure in NCM was frequently elevated; when described, CSF typically had elevated protein and normal glucose levels and a sterile leukocytosis. Seven of 11 patients had elevated CSF red blood cell counts* and five had xanthochromic fluid 21 ,22, 25,34,35; in some patients melanin granules rather than hemosiderin or elevated protein levels may have caused the yellow discoloration of fluid. 22 CSF cytology revealed malignant cells in only two of five patients 25 ,32 numerous "melanin~containing cells" were observed in one patient,29 and free melanin granules were found in two of three patients. 16,36 Electroencephalographic studies frequently demonstrated either focal or generalized abnormalities. Hydrocephalus and mass lesions were identified with various imaging procedures. With tumors involving the meninges, computed tomography with contrast most commonly shows enhancement of the leptomeninges overlying the brain stem and basilar cisterns,68 and this has been described in meningeal melanosis. 39 Magnetic resonance imaging with gadolinium contrast (MRI-Gd) has been found to be more sensitive than computed tomography and noncontrast MRI in screening certain intracerebral lesions, and it is the diagnostic procedure of choice in the evaluation of hydrocephalus. 69-71 MRI-Gd has also been useful in the evaluation of extracerebral tumors, such as intraventricular and meningeal tumors, and may detect early meningeal thickening.29, 71, 72
"References
21, 26, 35, 36,40,41,43.
Volume 24 Number 5, Part 1 May 1991
Neurocutaneous melanosis 753
TREATMENT AND PROGNOSIS
RECOMMENDATIONS
Rarely NCM may be asymptomatic and discovered incidentally at postmortem examination37,65; the long-term prognosis for these patients is unknown. All other patients described in the literature had neurologic symptoms, and in the vast majority the clinical course was characterized by progressive deterioration and early death. Only 8% (3 of 39) of the patients were living when their cases were reported. 26 ,27, 44 Of the 36 who died, 70% died before 10 years of age; only 4 lived beyond the age of 25. 16, 30,32,40 The interval between the patient's age at initial presentation with NCM and death ranged from immediate2 to 21 years 42 ; more than half (19 of 35; 54%) of the fatalities occurred within 3 years of their initial presentation with neurologic manifestations. Unfortunately antineoplastic therapy has not significantly ameliorated symptoms and has not altered the rapid course of NCM; all seven patients who received radiation or chemotherapy died within the first year of treatment. * In general, patients who were treated with palliative surgical measures, such as shunt placement to reduce intracranial pressure, improved at least transiently.24-27,39 No case reports described extensive cutaneous surgery for reduction of skin lesions in patients known to have NCM; in three patients excisional operations had been performed in the first 2 years of life without complications24,25, 40; in one patient NCM was "unmasked," with the development of seizures during premedication in preparation for surgery.40 Even in the absence of N CM, the role of extensive surgical procedures in giant congenital melanocytic nevi excision is controversial. Most authors6,8-10, 12, 14, 73 advocate surgery to reduce the risk of melanoma estimated to occur in a significant number of patients (approximately 5% to 15%).9,74 In addition, surgery may improve the cosmetic appearance of affected patients. An estimated 40% to 62% of patients with NCM will develop leptomeningeal melanoma, 5 and even in the presence of benign CNS lesions the condition is usually clinically malignant. When the poor prognosis, the risks of general anesthesia,75 and the physical and psychological trauma of surgery76 are considered, prophylactic cutaneous surgery is probably rarely, if ever, indicated in symptomatic cases of NCM..
Dermatologists, in their follow-up of patients with large or numerous congenital melanocytic nevi, are in a position to detect the development of neurologic involvement early in the course and may have an impact on the quality of life for these patients. Most patients are seen in early infancy; they should be seen relatively frequently, as dictated by the appearance of, and approach to, the cutaneous lesions. Open communication between the dermatologist and the pediatrician could facilitate early detection of neurologic manifestations. Physicians should be watchful for signs and symptoms of increased intracranial pressure. which include lethargy, irritability, headache, recurrent vomiting, seizures, and photophobia, and should also look for evidence of developmental delay. Head circumference should be measured regularly because disproportionate increase could be an early sign ofhydrocephalus. The second peak age of presentation with neurologic manifestations occurs in the second and third decades of life, when patients tend to present with the signs and symptoms of intracranial mass lesions and spinal cord compression, as well as increased intracranial pressure. The yield and cost-effectiveness of CNS evaluation by CSF cytology and MRI-Gd scanning are uncertain because the incidence of CNS involvement in the population at risk is not known, and no specific recommendations can be made regarding indications for CNS evaluation before excisional skin surgery. Our review suggests that patients with large or multiple nevi on the head, neck, or posterior midline may have an increased risk of leptomeningeal melanosis detectable by MRI-Gd. This would be a fruitful area for further investigation.
*References
16,23,25,31,32,34,40.
REFERENCES
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